CN110234349A - Specifically combine the antibody and application thereof of human IL-15 - Google Patents

Specifically combine the antibody and application thereof of human IL-15 Download PDF

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CN110234349A
CN110234349A CN201780079926.6A CN201780079926A CN110234349A CN 110234349 A CN110234349 A CN 110234349A CN 201780079926 A CN201780079926 A CN 201780079926A CN 110234349 A CN110234349 A CN 110234349A
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antibody
ser
amino acid
acid sequence
seq
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CN110234349B (en
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大卫·约瑟·西蒙·莱恩
马修·波拉德
安东尼·杰拉德·道尔
林恩·多萝西·普尔顿
亚当·威廉·克拉克
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Cephalon LLC
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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
    • G01N33/6863—Cytokines, i.e. immune system proteins modifying a biological response such as cell growth proliferation or differentiation, e.g. TNF, CNF, GM-CSF, lymphotoxin, MIF or their receptors
    • G01N33/6869—Interleukin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A61P29/02—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] without antiinflammatory effect
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/04—Immunostimulants
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/24—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against cytokines, lymphokines or interferons
    • C07K16/244—Interleukins [IL]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/21—Immunoglobulins specific features characterized by taxonomic origin from primates, e.g. man
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/55—Fab or Fab'
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
    • C07K2317/565—Complementarity determining region [CDR]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
    • C07K2317/567—Framework region [FR]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
    • C07K2317/92—Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
    • G01N2333/52—Assays involving cytokines
    • G01N2333/54—Interleukins [IL]
    • G01N2333/5443—IL-15

Abstract

Provide the recombinant antibodies for specifically combining the compound of IL-15 and IL-15 and IL-15 receptor alpha.The antibody inhibits immune cell propagation, and can be used in treating any autoimmune or inflammatory disease or illness of IL-15 imbalance, including chylous diarrhea.

Description

Specifically combine the antibody and application thereof of human IL-15
The reference of sequence table
The application includes sequence table, is generated on December 18th, 2017, entitled 2873.273PC01_ SequenceListing_ST25.text, 215,523 byte of size.The sequence table is incorporated by reference.
Technical field
The disclosure relates generally to the fields that recombinant antibodies generate.More particularly, this disclosure relates to specifically combine people The recombinant antibodies of IL-15 (not compound or compound with IL-15 receptor alpha).
Background technique
Various bibliography are referred to throughout the specification, including patent, the patent application of announcement, technical article, sequence Column accession number and other bibliography.Each such bibliography is integrally incorporated by reference, and for all purposes.
Cytokine interleukin 15 (IL-15) is the member of IL-2 superfamily, by many cell types and tissue (including monocyte, macrophage, Dendritic Cells (DC), horn cell, fibroblast and nerve cell) secretion.IL- 15 believe with its sending by the compound knot merga pass of IL-2 receptor β chain (CD122) and common γ chain (γ-C, CD132) composition Number.In vitro, IL-15 and IL-2 share several bioactivity.It in vivo, is by complete relative to specificity of the IL-2 to IL-15 It is mentioned at the unique privately owned α chain receptor (IL-15R α) of IL-15R α/IL-2R β γ heterotrimer high-affinity receptor compound It supplies.
Isolate IL-15 from the synovial tissue of patient with rheumatoid arthritis, it was reported that its inflammation inducing cell because Sub and chemotactic factor (CF) such as tumor necrosis factor-alpha, IL-1 β (Waldman TA (2004) Arthritis Res.Ther.6: 174-177).Block IL-15 activity that psoriasis is caused to subside in the xenograft mouse model of mankind's psoriasis (Villadsen LS et al. (2003) J.Clin.Invest.112:1571-80).It was reported that being drenched with T cell bulky grain In bar cell leukemia, γ Δ/Δ t cell lymphoma patient, IL-15 complex levels increase (Chen J et al. (2012) Blood.119:137-143).
Using the mouse for lacking IL-15, researcher also shows to inhibit IL-15 signal transduction pathway can be several immune Illness (such as experimental autoimmune encephalomyelitis (the EAE of mediation；Multiple sclerosis model), colitis, inflammatory bowel Disease, psoriasis and arthritis) in prevention or treatment benefit are provided.
In mouse model, IL-15 is overexpressed in enterocyte causes chyle sample enteropathy.In human body, IL-15 table It is the mark of chylous diarrhea up to up-regulation.Compared with normal healthy controls and the celiac patients treated through gluten-free diet, IL-15 is being suffered from Be overexpressed in the lamina propria and enteric epithelium of the patient of the activity chylous diarrhea of untreated, and the IL-15 level in enteron aisle with Mucosal injury degree is related (Abadie V et al. (2014) Immunol.Rev.260:221-234).
DISC0280 is a kind of effective anti-IL-15 antibody, has opposite effect mechanism in vitro and in vivo.(Finch DK et al. (2011) Br.J.Pharmacol.162:480-490).Disadvantageously, the IL-15 on discovery DISC0280 and IL-15 Receptor alpha binding site combines, this allows DISC0280 trans- presentation IL-15 in vivo, similar to soluble IL-15 receptor alpha Trans- presentation.Therefore, DISC0280 serves as the agonist of IL-15 in vivo.
Two kinds of anti-IL-15 antibody, which have been described, can neutralize the activity of IL-15 without the knot with IL-15 and IL-15R α Close competition.I-II of the complete anti-IL-15 antibody A MG 714 (Amgen) of human monoclonal in Active rheumatoid arthritis patient Shown in phase dose escalation trial Disease Activity improve (Baslund B et al. (2005) Arthritis Rheum.52: 2686-2692).The humanized antibody for being also described to entitled huB-E29 blocks IL-15 living in vitro and in vivo in mouse model Property, without and IL-15 and IL-15R α combination compete (WO 16/001275).
Examining the terminal of the clinical test of the new treatment for chylous diarrhea treatment is: a) such as by V/C than measured, bran The mitigation of the intestinal mucosa injury of matter induction.V/C is the intestinal villi length from the acquirement of intestines biopsy samples relative to Crypt depth Morphometry measurement.(b) as measured by the counting of intraepithelial lymphocyte in histotomy (IEL), seitan is induced Mucous membrane of small intestine inflammation mitigation.(c) the serum antibody such as anti-gliadin antibody and anti-rotation glutamine of seitan induction The reduction of enzyme autoantibody.As measured by aforementioned terminal, chylous diarrhea can effectively be treated by showing currently without therapeutic agent.This It is open to characterize antibody, the antibody mucous membrane of small intestine damage for mitigating seitan induction measured such as in rhesus macaque chylous diarrhea model Wound (improves V/C ratio), mitigates the mucous membrane of small intestine inflammation (reducing IEL to count) of seitan induction and reduces the serum antibody of seitan induction (reducing anti-gliadin antibody).The antibody of the disclosure is to be related to the trouble of the inflammatory disease of IL-15 with other with chylous diarrhea Person provides new treatment.
Summary of the invention
In a first aspect, the disclosure characterizes the antibody comprising variable heavy chain and variable light, the antibody specificity In conjunction with the epitope (for example, wherein IL-15 and IL-15R α are compound) of the Gin108 residue comprising human IL-15.In some embodiments In, human IL-15 includes the amino acid sequence of SEQ ID NO:511.In some embodiments, epitope also may include human IL-15 112 residue of Ser7 and Asn (for example, wherein IL-15 and IL-15R α it is compound).In some embodiments, antibody is preferably There is affinity to epitope comprising as what is measured by surface plasmon resonance is less than about 1.8x10-9The KD of M.One In a little embodiments, KD is smaller than about 1.0x10-9M.In some embodiments, antibody preferably has affinity to epitope, It includes as what is measured by surface plasmon resonance is less than about 2x10-10The KD of M.In some embodiments, such as pass through What surface plasmon resonance was measured, KD can be about 1.6x10-10M to about 1.8x10-10M.In some embodiments, certainly So in killing (NK) cell proliferating determining, antibody can be to be less than about 900pM (including about 0.1pM to the IC of about 900pM)50Inhibit The proliferation of NK cell (such as NK-92 cell).In some embodiments, in NK cell proliferating determining, antibody can be with about The IC of 1pM to about 60pM50Inhibit the proliferation of NK cell.In some embodiments, in NK cell proliferating determining, antibody can be with With about 5pM to the IC of about 35pM50Inhibit the proliferation of NK cell.In NK cell proliferating determining, antibody can be with about 5pM to about The IC of 25pM50Inhibit the proliferation of NK cell.Antibody can neutralize IL-15.Antibody can reduce circulation NK cell.
On the other hand, the disclosure characterizes antibody, combines human IL-15 to the antibody specificity, and include containing The HCDR1 of the amino acid sequence of SEQ ID NO:16, amino acid sequence containing SEQ ID NO:17 HCDR2, contain SEQ The HCDR3 of the amino acid sequence of ID NO:20, amino acid sequence containing SEQ ID NO:25 LCDR1, contain SEQ ID The LCDR3 of the LCDR2 of the amino acid sequence of NO:28 and the amino acid sequence containing SEQ ID NO:29.Human IL-15 can be with IL-15 receptor alpha is compound.Antibody is IL-15 antagonist.Additionally provide the polynucleotides for encoding such antibody.
In some embodiments, antibody is (such as comprising respectively containing SEQ ID NO:16,17,20,25,28 and 29 The antibody of HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3 of amino acid sequence) it may include containing SEQ ID NO:18 Amino acid sequence HCDR2.In some embodiments, antibody (such as comprising respectively contain SEQ ID NO:16,17 or 18, the antibody of HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3 of 20,25,28 and 29 amino acid sequence) it can wrap The LCDR3 of LCDR1 containing the amino acid sequence containing SEQ ID NO:27 and the amino acid sequence containing SEQ ID NO:31.? In some embodiments, antibody may include the heavy chain variable region of the amino acid sequence containing SEQ ID NO:454 and contain SEQ The light chain variable region of the amino acid sequence of ID NO:8, and/or may include the amino acid sequence containing SEQ ID NO:9 Light chain.In some embodiments, antibody is (such as comprising respectively containing SEQ ID NO:16,17 or 18,20,25,28 and 29 The antibody of HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3 of amino acid sequence) it may include containing SEQ ID NO:12 Or the heavy chain FR3 of the amino acid sequence of SEQ ID NO:13.Additionally provide the polynucleotides for encoding such antibody.
In some embodiments, antibody (such as comprising respectively contain the and of SEQ ID NO:16,17 or 18,20,25,28 The antibody of HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3 of 29 amino acid sequence) it may include containing SEQ ID The LCDR3 of the LCDR1 of the amino acid sequence of NO:26 and the amino acid sequence containing SEQ ID NO:31.In some embodiments In, antibody (such as include the amino acid sequence respectively containing SEQ ID NO:16,17 or 18,20,25 or 26,28 and 29 or 31 HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3 antibody) may include the amino acid sequence containing SEQ ID NO:4 The light chain variable region of the heavy chain variable region of column and the amino acid sequence containing SEQ ID NO:455, and/or may include containing The light chain of the amino acid sequence of SEQ ID NO:456.Additionally provide the polynucleotides for encoding such antibody.
In some embodiments, antibody (such as comprising respectively contain the and of SEQ ID NO:16,17 or 18,20,25,28 The antibody of HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3 of 29 amino acid sequence) it may include containing SEQ ID The LCDR3 of the LCDR1 of the amino acid sequence of NO:27 and the amino acid sequence containing SEQ ID NO:30.In some embodiments In, antibody (such as HCDR1 comprising the amino acid sequence respectively containing SEQ ID NO:16,17 or 18,20,27,28 and 30, The antibody of HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3) may include the amino acid sequence containing SEQ ID NO:4 heavy chain The light chain variable region of variable region and the amino acid sequence containing SEQ ID NO:457, and/or may include containing SEQ ID The light chain of the amino acid sequence of NO:458.Additionally provide the polynucleotides for encoding such antibody.
In some embodiments, antibody (such as comprising respectively contain the and of SEQ ID NO:16,17 or 18,20,25,28 The antibody of HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3 of 29 amino acid sequence) it may include containing SEQ ID The LCDR3 of the LCDR1 of the amino acid sequence of NO:27 and the amino acid sequence containing SEQ ID NO:29, wherein SEQ ID NO: 29 Xaa5 is Phe (such as SEQ ID NO:519).In some embodiments, antibody (such as comprising respectively contain SEQ ID HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3 of the amino acid sequence of NO:16,17 or 18,20,27,28 and 519 Antibody) may include the heavy chain variable region of the amino acid sequence containing SEQ ID NO:4 and the amino containing SEQ ID NO:459 The light chain variable region of acid sequence, and/or may include the light chain of the amino acid sequence containing SEQ ID NO:460.Also provide The polynucleotides of the such antibody of coding.
In some embodiments, antibody (such as comprising respectively contain the and of SEQ ID NO:16,17 or 18,20,25,28 HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3 of 29 amino acid sequence and optional contain SEQ ID NO: The antibody of the HFR3 of 12 or 13 amino acid sequence) it may include the LCDR1 of the amino acid sequence containing SEQ ID NO:26 and contain There is the LCDR3 of the amino acid sequence of SEQ ID NO:30.In some embodiments, (such as comprising containing SEQ ID respectively HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3's of the amino acid sequence of NO:16,17 or 18,20,26,28 and 30 Antibody) antibody may include the HCDR2 of the amino acid sequence containing SEQ ID NO:18 and the amino acid containing SEQ ID NO:13 The heavy chain FR3 of sequence.In some embodiments, antibody (such as comprising respectively contain SEQ ID NO:16,17 or 18,20, 26, HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3 of 28 and 30 amino acid sequence and optional contain SEQ The antibody of the HFR3 of the amino acid sequence of ID NO:12 or 13) may include the amino acid sequence containing SEQ ID NO:4 heavy chain Variable region.In some embodiments, antibody (such as comprising respectively contain SEQ ID NO:16,17 or 18,20,26,28 and 30 Amino acid sequence HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3 and optional contain SEQ ID NO:12 13 amino acid sequence HFR3 antibody or heavy chain variable region comprising the amino acid sequence containing SEQ ID NO:4 it is anti- Body) it may include the light chain variable region of the amino acid sequence containing SEQ ID NO:5, and/or may include containing SEQ ID The light chain of the amino acid sequence of NO:6.Additionally provide the polynucleotides for encoding such antibody.
In some embodiments, antibody is (such as comprising respectively containing SEQ ID NO:16,17,20,25,28 and 29 HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3 of amino acid sequence and optional contain SEQ ID NO:12's The antibody of the HFR3 of amino acid sequence) it may include the HCDR2 of the amino acid sequence containing SEQ ID NO:19, contain SEQ ID The LCDR1 of the amino acid sequence of NO:27, amino acid sequence containing SEQ ID NO:31 LCDR3 and contain SEQ ID NO: The heavy chain FR3 of 14 amino acid sequence.In some embodiments, antibody (such as comprising containing SEQ ID NO:16,19,20, 27, HCR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3 of 28 and 31 amino acid sequence and contain SEQ ID NO: The antibody of the HFR3 of 14 amino acid sequence) it may include the heavy chain variable region of the amino acid sequence containing SEQ ID NO:7 and contain There is the light chain variable region of the amino acid sequence of SEQ ID NO:8, and/or may include the amino acid containing SEQ ID NO:9 The light chain of sequence.Additionally provide the polynucleotides for encoding such antibody.
On the other hand, the disclosure characterizes antibody, combine to the antibody specificity human IL-15 (such as with IL-15R α Compound IL-15), and include the heavy chain variable region of the amino acid sequence containing SEQ ID NO:1 and containing SEQ ID NO:2 Amino acid sequence light chain variable region.In some embodiments, antibody includes the amino acid sequence containing SEQ ID NO:4 Heavy chain variable region and the amino acid sequence containing SEQ ID NO:5 light chain variable region.In some embodiments, antibody packet Heavy chain variable region containing the amino acid sequence containing SEQ ID NO:454 and the amino acid sequence containing SEQ ID NO:8 it is light Chain variable region.In some embodiments, antibody includes the heavy chain variable region of the amino acid sequence containing SEQ ID NO:4 and contains There is the light chain variable region of the amino acid sequence of SEQ ID NO:455.In some embodiments, antibody includes to contain SEQ ID The light chain variable region of the heavy chain variable region of the amino acid sequence of NO:4 and the amino acid sequence containing SEQ ID NO:457.One In a little embodiments, antibody includes the heavy chain variable region of the amino acid sequence containing SEQ ID NO:4 and contains SEQ ID NO: The light chain variable region of 459 amino acid sequence.Additionally provide the polynucleotides for encoding such antibody.
On the other hand, the disclosure characterizes antibody, combine to the antibody specificity human IL-15 (such as with IL-15R α Compound IL-15), and include the heavy chain variable region of the amino acid sequence containing SEQ ID NO:4 and containing SEQ ID NO:8 Amino acid sequence light chain variable region；The heavy chain variable region of amino acid sequence containing SEQ ID NO:4 and contain SEQ ID The light chain variable region of the amino acid sequence of NO:503；The heavy chain variable region of amino acid sequence containing SEQ ID NO:4 and contain The light chain variable region of the amino acid sequence of SEQ ID NO:505；The heavy chain variable region of amino acid sequence containing SEQ ID NO:4 With the light chain variable region of the amino acid sequence containing SEQ ID NO:507；The heavy chain of amino acid sequence containing SEQ ID NO:4 The light chain variable region of variable region and the amino acid sequence containing SEQ ID NO:509；Amino acid sequence containing SEQ ID NO:4 Heavy chain variable region and the amino acid sequence containing SEQ ID NO:510 light chain variable region；Ammonia containing SEQ ID NO:454 The light chain variable region of the heavy chain variable region of base acid sequence and the amino acid sequence containing SEQ ID NO:455；Contain SEQ ID The light chain variable region of the heavy chain variable region of the amino acid sequence of NO:454 and the amino acid sequence containing SEQ ID NO:503；Contain There are the heavy chain variable region of the amino acid sequence of SEQ ID NO:454 and the light chain of the amino acid sequence containing SEQ ID NO:457 Variable region；The heavy chain variable region of amino acid sequence containing SEQ ID NO:454 and amino acid sequence containing SEQ ID NO:505 The light chain variable region of column；The heavy chain variable region of amino acid sequence containing SEQ ID NO:454 and contain SEQ ID NO:506's The light chain variable region of amino acid sequence；The heavy chain variable region of amino acid sequence containing SEQ ID NO:454 and contain SEQ ID The light chain variable region of the amino acid sequence of NO:507；The heavy chain variable region of amino acid sequence containing SEQ ID NO:454 and contain There is the light chain variable region of the amino acid sequence of SEQ ID NO:5；The weight chain variable of amino acid sequence containing SEQ ID NO:454 The light chain variable region in area and the amino acid sequence containing SEQ ID NO:509；Or the amino acid sequence containing SEQ ID NO:454 Heavy chain variable region and the amino acid sequence containing SEQ ID NO:510 light chain variable region.Additionally provide the such antibody of coding Polynucleotides.
The consensus sequence of antibody VH is SEQ ID NO:1, and covers the VH of SEQ ID NO:4 and SEQ ID NO:454 Sequence.The consensus sequence of antibody VL is SEQ ID NO:2, and covers SEQ ID NO:5, SEQ ID NO:8, SEQ ID NO: 455, the VL sequence of SEQ ID NO:457 and SEQ ID NO:459.The consensus sequence of light chain of antibody is SEQ ID NO:3, and Cover the L chain sequence of SEQ ID NO:6, SEQ ID NO:9, SEQ ID NO:456, SEQ ID NO:458 and SEQ ID NO:460 Column.The consensus sequence of antibody VH FR3 is SEQ ID NO:12, and covers the VH of SEQ ID NO:13 and SEQ ID NO:14 FR3 sequence.The consensus sequence of antibody VH CDR1 is SEQ ID NO:17, and covers SEQ ID NO:18 and SEQ ID NO: 19 VH sequence.The consensus sequence of antibody VL CDR1 is SEQ ID NO:25, and covers SEQ ID NO:26 and SEQ ID The VH sequence of NO:27.The consensus sequence of antibody VL CDR3 is SEQ ID NO:29, and covers SEQ ID NO:30 and SEQ The VH sequence of ID NO:31 and SEQ ID NO:519.
Any antibody of as described herein or illustration combination IL-15 (such as human IL-15 compound with IL-15R α), It may include IgG constant domain including those of any aforementioned paragraphs antibody.In some embodiments, IgG constant domain It may include IgG1 constant domain.In some embodiments, IgG1 constant domain may include SEQ ID NO:32, SEQ ID NO:33, SEQ ID NO:34, SEQ ID NO:35, SEQ ID NO:36, SEQ ID NO:37, SEQ ID NO:38 or SEQ ID NO:39.In some embodiments, IgG constant domain may include IgG2 constant domain.In some embodiments, IgG2 constant domain may include SEQ ID NO:40, SEQ ID NO:41, SEQ ID NO:42 or SEQ ID NO:43.One In a little embodiments, IgG constant domain may include IgG4 constant domain.In some embodiments, the constant structure of IgG4 Domain may include SEQ ID NO:44, SEQ ID NO:45, SEQ ID NO:46, SEQ ID NO:47, SEQ ID NO:48, SEQ ID NO:49, SEQ ID NO:50 or SEQ ID NO:51.
Any antibody of as described herein or illustration combination IL-15 (such as human IL-15 compound with IL-15R α), Including those of any aforementioned paragraphs antibody, the composition with carrier or excipient can be configured to.Carrier may include pharmacy Upper acceptable carrier.
In some embodiments, the method for treating chylous diarrhea includes combining IL-15 (example to subject in need application Such as human IL-15 compound with IL-15R α) antibody.Application IL-15 antibody can repair the mucous membrane of small intestine of subject.Apply IL- 15 antibody can increase the average fluff height and Crypt depth (V/C) ratio of subject.Application IL-15 antibody can increase tested The height of the intestinal villi of person.Application IL-15 antibody can reduce the anti-gliadin antibody of subject.It is anti-to apply IL-15 Body can repair the intestinal mucosa injury of the seitan induction of subject.
Any antibody of as described herein or illustration combination IL-15 (such as human IL-15 compound with IL-15R α), Including those of any aforementioned paragraphs antibody, a part that can be used as therapeutic scheme is administered to subject in need.Therefore, On the other hand, the disclosure characterizes the method with IL-15 Antybody therapy subject in need.Subject is preferably the mankind. Antibody can be used as a part application of therapeutic scheme, to treat any itself exempting from of IL-15 imbalance, particularly IL-15 up-regulation Epidemic disease or inflammatory disease or illness.
In some detailed embodiments, the method can be used for treating chylous diarrhea, and including applying to subject With as described herein or illustrate combination IL-15 (such as human IL-15 compound with IL-15R α) any antibody, including appoint Those of what aforementioned paragraphs antibody, the antibody may be in composition, and the composition may include pharmaceutically acceptable Carrier or excipient.In some embodiments, for repairing the subject for suffering from sensitive seitan, gluten or chylous diarrhea Mucous membrane of small intestine method include to subject's application as described herein or the combination IL-15 that illustrates is (such as multiple with IL-15R α The human IL-15 of conjunction) those of any antibody, including any aforementioned paragraphs antibody, the antibody may be in composition, institute Stating composition may include pharmaceutically acceptable carrier or excipient.In some embodiments, seitan is suffered from for increasing The average fluff height of subject and the method for Crypt depth (V/C) ratio of sensitive, gluten or chylous diarrhea include to tested Person applies any antibody of the combination IL-15 (such as human IL-15 compound with IL-15R α) as described herein or illustrated, packet Those of any aforementioned paragraphs antibody is included, the antibody may be in composition, and the composition, which may include, pharmaceutically may be used The carrier or excipient of receiving.In some embodiments, for increase suffer from seitan sensitive, gluten or chylous diarrhea by The method of the small intestinal villous height of examination person include to subject application as described herein or illustrate combination IL-15 (such as with IL-15R α compound human IL-15) those of any antibody, including any aforementioned paragraphs antibody, the antibody may be at group It closes in object, the composition may include pharmaceutically acceptable carrier or excipient.In some embodiments, for reducing The method of the anti-gliadin antibody of subject in need includes to the knot that subject's application is as described herein or illustrates Those of any antibody, including any aforementioned paragraphs of IL-15 (such as human IL-15 compound with IL-15R α) antibody is closed, it is described Antibody may be in composition, and the composition may include pharmaceutically acceptable carrier or excipient.In some implementations In scheme, the method for the intestinal mucosa injury for repairing seitan induction includes as described herein to subject's application or illustrates Those of any antibody, including any aforementioned paragraphs of combination IL-15 (such as human IL-15 compound with IL-15R α) antibody, The antibody may be in composition, and the composition may include pharmaceutically acceptable carrier or excipient.Some In embodiment, subject sensitive, gluten or chylous diarrhea with seitan.In some embodiments, the method can be with For treating intractable chylous diarrhea, and including to subject's application as described herein or illustrate combination IL-15 (such as with IL-15R α compound human IL-15) those of any antibody, including any aforementioned paragraphs antibody, the antibody may be at group It closes in object, the composition may include pharmaceutically acceptable carrier or excipient.In some embodiments, the method It can be used for treating rheumatoid arthritis, and including applying the combination IL-15 as described herein or illustrated to subject Those of any antibody, including any aforementioned paragraphs of (such as human IL-15 compound with IL-15R α) antibody, the antibody can With in composition, the composition may include pharmaceutically acceptable carrier or excipient.In some embodiments, The method can be used for treating psoriasis, and including applying the combination IL-15 as described herein or illustrated to subject Those of any antibody, including any aforementioned paragraphs of (such as human IL-15 compound with IL-15R α) antibody, the antibody can With in composition, the composition may include pharmaceutically acceptable carrier or excipient.In some embodiments, The method can be used for treating inflammatory bowel disease, and including applying the combination IL- as described herein or illustrated to subject Those of any antibody, including any aforementioned paragraphs of 15 (such as human IL-15s compound with IL-15R α) antibody, the antibody It may be in composition, the composition may include pharmaceutically acceptable carrier or excipient.In some embodiments In, the method can be used for treating type 1 diabetes, and including applying the combination as described herein or illustrated to subject Those of any antibody, including any aforementioned paragraphs of IL-15 (such as human IL-15 compound with IL-15R α) antibody, it is described anti- Body may be in composition, and the composition may include pharmaceutically acceptable carrier or excipient.In some embodiment party In case, the method can be used for treating alopecia areata disease, and including applying the combination as described herein or illustrated to subject Those of any antibody, including any aforementioned paragraphs of IL-15 (such as human IL-15 compound with IL-15R α) antibody, it is described anti- Body may be in composition, and the composition may include pharmaceutically acceptable carrier or excipient.In some embodiment party In case, the method can be used for treating T cell large granular lymphocyte leukaemia, and including applying to subject such as this Any antibody of combination IL-15 (such as human IL-15 compound with IL-15 receptor alpha) that is literary described or illustrating, including it is any before Those of paragraph antibody is stated, the antibody may be in composition, and the composition may include pharmaceutically acceptable load Agent or excipient.In some embodiments, the method can be used for treating or inhibiting seitan exposure, such as quick with seitan The symptom of seitan exposure in the patient of sense or allergy, and including applying the combination as described herein or illustrated to subject Those of any antibody, including any aforementioned paragraphs of IL-15 (such as human IL-15 compound with IL-15R α) antibody, it is described anti- Body may be in composition, and the composition may include pharmaceutically acceptable carrier or excipient.The one of seitan exposure Kind or a variety of symptoms may include courbature, somatalgia, arthralgia, fatigue, aerogastria, intestines gas, nausea, colic pain, constipation, diarrhea, One of fash, headache, migraine, depression and anxiety, brain mist and/or agitation are a variety of.Referring to Biesiekierski JR (2015) United European Gastroenterol.J.3:160-165.
Any antibody of as described herein or illustration combination IL-15 (such as human IL-15 compound with IL-15R α), Including those of any aforementioned paragraphs antibody, can be used for manufacturing drug.Any such antibody can be used for treating IL-15 imbalance Any autoimmune or inflammatory disease or illness.In some embodiments, antibody can be used for treating chylous diarrhea or for making Make the drug for treating chylous diarrhea.Antibody can be used for treating intractable chylous diarrhea or for manufacturing for treating intractable chyle The drug rushed down.In some embodiments, antibody can be used for treating rheumatoid arthritis or for manufacturing for treating class wind The drug of wet arthritis.In some embodiments, antibody can be used for treating psoriasis or for manufacturing for treating silver-colored bits The drug of disease.In some embodiments, antibody can be used for treating inflammatory bowel disease or for manufacturing for treating inflammatory bowel disease Drug.In some embodiments, antibody can be used for treating type 1 diabetes or for manufacturing the medicine for treating type 1 diabetes Object.In some embodiments, antibody can be used for treating alopecia areata disease or for manufacturing the drug for treating alopecia areata disease.Some In embodiment, antibody can be used for treating T cell large granular lymphocyte leukaemia or big for treating T cell for manufacturing The drug of granular lymphocytic leukemia.
Any antibody of as described herein or illustration combination IL-15 (such as human IL-15 compound with IL-15R α), Including those of any aforementioned paragraphs antibody, can be used for detecting from subject separate tissue sample in IL-15 (optionally It is compound with IL-15R α) in-vitro method, the method includes contacting antibody to be formed with the tissue sample separated from subject Compound in antibody-IL-15 compound (optionally further compound with IL-15 receptor alpha), and detection tissue sample.Such as Those of any antibody, including any aforementioned paragraphs of combination IL-15 described or illustrated herein antibody, can be used for detecting From the in-vitro method of IL-15 and IL-15 receptor alpha compound in the tissue sample that subject separates, the method includes making to resist Body is contacted with the tissue sample separated from subject to form the antibody-antigene of antibody and IL-15 and IL-15 receptor alpha compound Antibody-antigen complex in compound, and detection tissue sample.
On the other hand, the disclosure also characterizes the cell of conversion, the cell expression of the conversion as described herein or Those of any antibody, including any aforementioned paragraphs of the combination IL-15 (such as human IL-15 compound with IL-15R α) of illustration Antibody.In some embodiments, the cell of conversion can be mammalian cell.In some embodiments, mammal Cell can be Chinese hamster ovary cell.
On the other hand, the disclosure also characterizes polynucleotides, and the polynucleotide encoding is as described herein or illustrates Those of any antibody, including any aforementioned paragraphs of combination IL-15 (such as human IL-15 compound with IL-15R α) antibody. In some embodiments, the polynucleotides of encoding antibody heavy variable region include the nucleic acid sequence of SEQ ID NO:517.One In a little embodiments, the polynucleotides of encoding antibody light variable region include the nucleic acid sequence of SEQ ID NO:518.It additionally provides Carrier comprising these polynucleotides.Additionally provide the cell comprising these polynucleotides or carrier.It additionally provides comprising multicore The cell of thuja acid, the polynucleotides include coding as described herein or the combination IL-15 that illustrates is (such as multiple with IL-15R α The human IL-15 of conjunction) antibody, the nucleic acid of the variable heavy chain including those of any aforementioned paragraphs antibody and encoding said antibody The nucleic acid of variable light.The nucleic acid of the nucleic acid and coding variable light that encode variable heavy chain can be on identical carrier or not On same carrier.
Detailed description of the invention
Fig. 1 shows anti-IL-15 antibody and human IL-15 and IL-15 receptor alpha compound or the knot of not compound IL-15R α It closes.Representative doma supernatant and not compound recombined human IL-15R α are measured by cell ELISA (cELISA) and ELISA Or the combination of recombination IL-15 and IL-15 receptor alpha compound.As a result it is indicated with Relative fluorescence units.
Fig. 2A and Fig. 2 B shows anti-IL-15 antibody and inhibits to the dose response of the IL-15 CTLL-2 proliferation mediated.Fig. 2A The inhibition with the anti-IL-15 antibody of the diluted representativeness of 2000,200 and 20pM to the IL-15 CTLL-2 proliferation mediated is shown, and And Fig. 2 B shows the inhibition in 72 hours in full dose response.As a result relative light units are expressed as.
Fig. 3 shows representative anti-IL-15 antibody, AMG714 or isotype controls (anti-KLH C3 IgG1) and is situated between to IL-15 The inhibition for the NK-92 proliferation led.Reading was read at the 72nd hour, and was expressed as relative light units.As a result 3 repetitions are expressed as Average value ± error.
Fig. 4-Figure 33 shows anti-IL-15 variantSpectrum, details that antibody capture is horizontal, single-point is affine Power measured value and sequence variation relative to parental antibody (antibody 4).
Figure 34 A, Figure 34 B and Figure 34 C show anti-IL-15 antibody variants, detail it relative to parental antibody (antibody 4) Heavy chain and light chain amino acid replace.
Figure 35, which is shown, relative to parental antibody (antibody 4) and other anti-IL-15 antibody there is improved IL-15 to mediate 4 variant of antibody of NK-92 Proliferation Ability.Reading is read after 72 hours, and is expressed as relative light units.
Figure 36 shows the combination power of the combination of 4 variant of antibody and AMG714 and IL-15 and IL-15 receptor alpha compound It learns.Binding kinetics are measured using surface plasmon resonance in Biacore T200 (GE Healthcare) system.Antibody 4 variants are with affinity combination IL-15 compound more higher than AMG714.
Figure 37 shows the comparison of anti-IL-15 antibody in the measurement based on NK-92 cell.Anti- IL-15 is anti-within 48 hours The inhibition of the body NK-92 proliferation compound-mediated to the IL-15 of 25pM is expressed as relative light units.70 variant of antibody is imitated each other Power is similar, and its IC-50 value is lower than AMG-714.
Figure 38 shows the surface exposed residue on IL-15, these residues are converted into alanine by direct mutagenesis, and with Human IL-15 R α existsIt is co-expressed in F cell.?In T200 (GE Healthcare) system The combination of the IL-15 variant of anti-IL-15 antibody and purifying is evaluated using surface plasmon resonance.As quickly dissociated or faster What dissociation rate was characterized, AMG714 is not combined or is combined horizontal significantly reduce with E98A, Q101A, H105A or Q108A.Such as drop What low association rate and quick dissociation were characterized, the combination level of antibody 70a and Q108A are low.
Figure 39 A and Figure 39 B show the crystal of antibody 70a.FAb/IL-15 compound and level Four IL-15 receptor complex Structure.(Figure 39 A) combines the cartoon of the variable region of the antibody 70a.FAb of human IL-15 to indicate, front view and side view.(Figure 39 B) The quaternary structure of functional IL-15 compound.In conjunction with IL-15R α, IL-2R β and IL-2R γ human IL-15 (pdb code, Cartoon 4GS7) indicates.The combination of antibody 70a.FAb destruction IL-15 and IL-2R β and IL-2R γ.Antibody 70a FAb and IL- The IL-15 of the distal end 15R α is combined, and can combine IL-15/IL-15R α compound.
Figure 39 C, Figure 39 D and Figure 39 E show the pass with the IL-15 of antibody 70a, IL-2R γ and IL-2R β interaction Bond closes residue.Only describe and numbered and the IL-15 residue contacted with each chaperone is bonded by hydrogen.(Figure 39 C) IL-15 Residue (Figure 39 D) for interacting with antibody 70a FAb mediates the selected IL-15 being bonded with the hydrogen of IL-2R γ residual Base, including Q108, N112.(Figure 39 E) IL-15 residue S7 and IL-2R β forms hydrogen bond.
Figure 39 F, Figure 39 G and Figure 39 H show the crystal structure of human IL-15 Yu antibody 70a.(Figure 39 F) is shown and people IL- The cartoon of the 15 antibody FAb combined indicates.Triple tyrosine motifs in (Figure 39 G) CDRH2 comprising Y52/54/56 be antibody with The key combination determinant of human IL-15.The feature of the YYY motif of (Figure 39 H) from antibody 70a, which mediates and human IL-15 Interaction.The motif covers and protects the hydrophobic residue around IL-15 spiral 4, prevents solvation.Participate in the interaction IL-15 in side chain and the CDRH2 of residue indicated respectively with white stick and black stick.
Figure 40 shows the combination of antibody 70 variant and human IL-15.Anti- IL- is evaluated in following person monocytic cell's subgroup The extracellular and intracellular IL-15 of 15mAb is combined: classical monocyte, intermediate monocyte and non-classical monocyte.Dividing It include anti-KLH C3IgG1 isotype controls (solid) in analysis.Representative donor A data are shown.
Figure 41 shows in mouse exemplary anti-IL-15 antibody to the active inhibition of IL-15.It is being presented the result is that note Intermedium control or IL-15/IL-15R α-Fc compound are penetrated, exemplary anti-IL-15 antibody or anti-KLH C3IgG1 are then injected The counting of NK cell is recycled in the spleen of the mouse of isotype controls.As a result it is expressed as average value ± the standard deviation of every group of 8 animals Difference.
Figure 42 shows inhibition of the exemplary anti-IL-15 antibody to intermediate value circulation NK cell number in machin.Injection with Intermediate value in the machin of the exemplary anti-IL-15 antibody of 10mg/kg or 1mg/kg test recycles NK cell count.It is thin by NK The expression of born of the same parents' marker CD159a (NKG2A) and CD16 quantifies intermediate value circulation NK cell number.As a result it is expressed as each of every monkey A time point, solid line indicate the intermediate value NK cell number of every group (n=4).
Figure 43 A, Figure 43 B and Figure 43 C show various HCDR1, HCDR2 and HCDR3 combinations.
Figure 44 A, Figure 44 B and Figure 44 C show various LCDR1, LCDR2 and LCDR2 combinations.
Figure 45 A shows the researching and designing of rhesus macaque chylous diarrhea model, indicates each stage of two groups, terminal and anti- IL15 Antybody therapy.
Figure 45 B is shown as measured by the ratio between small intestinal villous height and Crypt depth (V/C), anti-IL15 Treatment is so that the intestinal mucosa injury of seitan induction mitigates.In the GD diet corresponding to 6 months, 35 days aIL-15 treatment the (the 1st Group rhesus macaque, TD35) and treatment (the 2nd group of rhesus macaque, TD61) in 61 days time point from two groups of rhesus macaquies collection intestines jejunum wedges Shape biopsy article determines V/C ratio using these biopsy articles.
Figure 45 C is shown as measured by the counting of intraepithelial lymphocyte in histotomy (IEL), and anti-IL15 is controlled It treats so that the mucous membrane of small intestine inflammation of seitan induction mitigates.Time point reflects 6 months GD diet, 3 months GFD diet, the 1st 61 days (TD61) after 35 days (TD35) and the 2nd group of rhesus macaque are treated after the anti-IL15 treatment of group rhesus macaque.Dotted line blue line indicates strong Health compares baseline.
Figure 45 D shows anti-IL15 and treats so that the serum antibody (anti-gliadin antibody) of seitan induction is reduced.AGA It is anti-gliadin antibody；TG2 is 2 autoantibody of anti-rotation glutaminase.The distance between time point was corresponding to two weeks Interval.Negative baseline level is represented by the dotted line.Anti- IL15 treatment starting is indicated by means of an arrow.
Specific embodiment
The use various terms related in terms of the disclosure in the whole instruction and claim.Unless in addition referring to Bright, otherwise these terms will be provided with their ordinary meanings in the art.Other terms being specifically defined will with herein The consistent mode of the definition of offer understands.
As used herein, unless explicitly stated otherwise, otherwise singular "one", "an" and "the" refer to including plural number For object.
Term " subject " and " patient " are used interchangeably and including any animals.It is preferred that mammal, including companion feed Newborn animal (such as cat, dog), farm mammal (such as pig, horse, ox), rodent (such as mouse, rabbit, rat, cavy) And non-human primate.The mankind are highly preferred.
As used herein, " IL-15 compound " refers to the interaction between IL-15 and IL-15 receptor alpha (IL-15R α).
" specificity " in the context of antibody-antigene interaction is not necessarily absolute instruction, but may be constructed table Show antibody to the relative terms of the degree of the selectivity of antigen.Antibody is mediated the specificity of antigen by the variable region of antibody, and And it is usually mediated by the complementary determining region of antibody (CDR).
The disclosure provides the antibody generated by recombination, combines free (not compound) people white to the antibody specificity Cytokine 15 (IL-15), and combined the IL-15-IL-15 compound of IL-15 receptor alpha (IL-15R α).Antibody is with high parent Its antigen is combined with power, and significantly reduces the immune cell propagation of IL-15 mediation.Antibodies Against IL-15.
Epitope on antibody combination human IL-15 (such as human IL-15 compound with IL-15R α) in a preferred aspect, the table Position includes at least the 108th glutamine.Epitope may also include human IL-15 (such as human IL-15 compound with IL-15R α) One or more of 7th serine and the 112nd asparagine.
The epitope that kinds of experiments epitope mapping procedure illustrates given antibody/antigen interaction can be used.These experiments Method includes mutagenesis (including alanine scanning), X-ray crystallography and various other methods well-known in the art.
The epitope to interact between antigen and antibody may include limiting atom present in antigen-antibody interaction to connect The space coordinate of touching.Epitope can be characterized by limiting the space coordinate of the atomic contacts between antigen and antibody.Epitope can By being characterized by specific criteria, such as by the amino acid residue of the distance between atom (such as non-hydrogen atom) restriction.
Derived from the X-ray that the space coordinate by the compound between antibody (such as FAb segment) and its antigen limits In the context of crystal structure, term epitope includes IL-15 residue, it is characterised in that has the hydrogen that water mediates between atom pair Key；?Between heteroatomic hydrogen bond；Or corresponding to donor/acceptor atom hydrogen bond in aromatic ring.Alternatively, such as The given IL-15 amino acid residue of fruit participates in hydrophobic interaction or Van der Waals interaction between atom pair, then it is assumed that it It is a part of epitope.
Epitope can also more generally include amino acid residue, will change antibody and antigen by another amino acid substitution Between the feature (for example, being scanned using alanine) that interacts.Mutant IL-15 can be used and carry out alanine scanning mutagenesis Experiment, wherein the various residues of IL-15 polypeptide are by alanine substitution.It, can by evaluating the combination of antibody and mutant IL-15 To evaluate the importance that specific IL-15 residue combines antibody.However, if nonpolarity occurs during antigen and antibody combine The assembling of side chain buried and lead to side chain to antigen, then the alanine mutation of the position may be in conjunction with not big shadow It rings.Although being reduced it is possible that alanine mutant causes antibody to combine, but this does not imply that residue is in contact, but The partial 3 d structure of IL-15 may be upset by the introducing of alanine.It may need such as by X-ray crystallography to compound Further structural analysis is carried out, to evaluate the contact residues between antibody and antigen.
Anti- IL-15 antibody is preferably able to inhibit, reduce or prevent immunocyte, such as natural kill (NK) cell and CD8+T cell proliferation.In some respects, in NK proliferation assay, anti-IL-15 antibody is with the IC less than about 900pM50Inhibit to increase It grows.In some respects, in NK proliferation assay, anti-IL-15 antibody is to be greater than 0pM and be less than about the IC of 900pM50Inhibit proliferaton. In NK proliferation assay, anti-IL-15 antibody can be with about 1pM to the IC of about 500pM50Inhibit proliferaton.In NK proliferation assay, resist IL-15 antibody can be with about 1pM to the IC of about 250pM50Inhibit proliferaton.In NK proliferation assay, anti-IL-15 antibody can be with about The IC of 1pM to about 200pM50Inhibit proliferaton.In NK proliferation assay, anti-IL-15 antibody can be with about 1pM to about 150pM's IC50Inhibit proliferaton.In NK proliferation assay, anti-IL-15 antibody can be with about 1pM to the IC of about 100pM50Inhibit proliferaton.In NK In proliferation assay, anti-IL-15 antibody is preferably with about 1pM to the IC of about 60pM50Inhibit proliferaton.In NK proliferation assay, anti-IL- 15 antibody are preferably with about 5pM to the IC of about 35pM50Inhibit proliferaton.In NK proliferation assay, anti-IL-15 antibody is preferably with about The IC of 5pM to about 30pM50Inhibit proliferaton.
As a part of suitable NK proliferation assay, answering for IL-15 and the IL-15 receptor alpha of suitable concentration can be used Close object culture cell (such as CTLL-2 cell) and proliferative induction.Therefore, CTLL-2 proliferation assay can be used to determine that antibody is proliferated The IC of inhibition50.Any anti-IL-15 antibody for being described herein or illustrating is added in cell culture, is then closed cell incubation The suitable period (including 48 hours), and then evaluate due to antibody exist caused by be proliferated or Proliferation Ability, including by Cell viability measurement.
As described herein or illustration, the amino acid position for distributing to CDR and FR can be according to Kabat Sequences Of Proteins of Immunological Interest, National Institutes of Health, Bethesda, Md., 1987 and 1991 (referred to herein as Kabat numbering system).In addition, the amino acid position for distributing to CDR and FR can According to Enhanced Chothia Numbering Scheme (www.bioinfo.org.uk/mdex.html).
According to the numbering system of Kabat, VH FR and CDR can be positioned such that: residue 1-30 (FR1), 31-35 (CDR1), 36-49 (FR2), 50-65 (CDR2), 66-94 (FR3), 95-102 (CDR3) and 103-113 (FR4), and VL FR and CDR are fixed Position is as follows: residue 1-23 (FR1), 24-34 (CDR1), 35-49 (FR2), 50-56 (CDR2), 57-88 (FR3), 89-97 (CDR3) and 98-107 (FR4).In some cases, the length of variable region can increase, and according to Kabat numbering system, It is specified that some amino acid can be followed by letter by number.This specification is not limited to the FR and CDR defined by Kabat numbering system, But including all numbering systems, including specification number system or Chothia et al. (1987) J.Mol.Biol.196:901-17 Numbering system；The numbering system of Chothia et al. (1989) Nature 342:877-83；And/or Al-Lazikani et al. (1997) numbering system of J.Mol.Biol.273:927-48；Honnegher et al. (2001) J.Mol.Biol., 309:657- 70 numbering system；Or discussed in Giudicelli et al. (1997) Nucleic Acids Res.25:206-11 IMGT system.CDR is defined according to Kabat numbering system in a preferred aspect,.
In some particular aspects, for any heavy chain CDR2 subdomain as described herein, according to Kabat numbering system, Five C-terminal amino acid may not directly participate in antigen binding, thus, it will be appreciated that any one in this five C-terminal amino acid It is a or multiple substantive adverse effect can be generated at non-confrontational former combine by another naturally occurring amino acid substitution.One A little aspects, for any light chain CDR1 subdomain as described herein, according to Kabat numbering system, four N-terminal amino acid can Antigen binding can not be directly participated in, thus, it will be appreciated that any one or more of this four amino acid can be by another day So existing amino acid substitution and non-confrontational former combine generates substantive adverse effect.For example, such as Padlan et al. (1995) FASEB is J.9:133-139 described, five C-terminal amino acid of heavy chain CDR2 and/or four N-terminal amino acid of light chain CDR1 Antigen binding may be not involved in.In some respects, heavy chain CDR2 and light chain CDR1 does not participate in antigen binding directly.
In some respects, IL-15 (such as human IL-15 compound with IL-15R α) is combined to antibody specificity, and includes The weight of the heavy chain variable region CDR1 of amino acid sequence containing SEQ ID NO:16, amino acid sequence containing SEQ ID NO:17 The heavy chain variable region CDR3 of chain variable region CDR2 and the amino acid sequence containing SEQ ID NO:20.In some preferred aspects, Antibody includes the heavy chain variable region CDR2 of the amino acid sequence containing SEQ ID NO:19, and resists in some preferred aspects, Body includes the heavy chain variable region CDR2 of the amino acid sequence containing SEQ ID NO:18.Antibody may include containing SEQ ID NO: 12, the heavy chain variable region FR3 of the amino acid sequence of SEQID NO:13 or SEQ ID NO:14.Antibody also may include light chain variable Area or light chain.Light chain variable region may include SEQ ID NO:2, SEQID NO:5, SEQ ID NO:8, SEQ ID NO:455, SEQ The amino acid sequence of ID NO:457 or SEQ ID NO:459.Light chain variable region may include SEQ ID NO:503, SEQID NO: 505, the amino acid sequence of SEQ ID NO:506, SEQ ID NO:507, SEQ ID NO:509 or SEQ ID NO:510.Light chain It may include SEQ ID NO:3, SEQ ID NO:6, SEQ ID NO:9, SEQ ID NO:456, SEQ ID NO:458 or SEQ ID The amino acid sequence of NO:460.
Heavy chain variable region CDR1 may include any in SEQ ID NO:453 or SEQ ID NO:52 to SEQ ID NO:135 A amino acid sequence.Heavy chain variable region CDR2 may include the amino of any of SEQ ID NO:136 to SEQ ID NO:226 Acid sequence.Heavy chain variable region CDR3 may include the amino acid sequence of any of SEQ ID NO:227 to SEQ ID NO:272. The appropriate combination of heavy chain variable region CDR1, CDR2 and CDR3 structural domain is shown in Figure 43 A to Figure 43 C.It can comprising such heavy chain Become the antibody of area CDR1, CDR2 or CDR3 structural domain, or includes heavy chain variable region CDR1, CDR2 shown in Figure 43 A to Figure 43 C Combined antibody with CDR3 also may include light chain variable region or light chain.Light chain variable region may include SEQ ID NO:2, SEQ ID The amino acid sequence of NO:5, SEQ ID NO:8, SEQ ID NO:455, SEQ ID NO:457 or SEQ ID NO:459.Light chain Variable region may include SEQ ID NO:503, SEQ ID NO:505, SEQ ID NO:506, SEQ ID NO:507, SEQ ID The amino acid sequence of NO:509 or SEQ ID NO:510.Light chain may include SEQ ID NO:3, SEQ ID NO:6, SEQ ID The amino acid sequence of NO:9, SEQ ID NO:456, SEQ ID NO:458 or SEQ ID NO:460.
In some respects, IL-15 (such as human IL-15 compound with IL-15R α) is combined to antibody specificity, and includes The light chain variable region CDRl of amino acid sequence containing SEQ ID NO:25, amino acid sequence containing SEQ ID NO:28 it is light The light chain variable region CDR3 of chain variable region CDR2 and the amino acid sequence containing SEQ ID NO:29.In some preferred aspects, Antibody includes the light chain variable region CDR1 of the amino acid sequence containing SEQ ID NO:27, and resists in some preferred aspects, Body includes the light chain variable region CDR1 of the amino acid sequence containing SEQ ID NO:26.Antibody includes in some preferred aspects, The light chain variable region CDR3 of amino acid sequence containing SEQ ID NO:31, and antibody contains in some preferred aspects, There is the light chain variable region CDR3 of the amino acid sequence of SEQ ID NO:30.Antibody also may include heavy chain variable region.Heavy chain variable region It may include the amino acid sequence of SEQ ID NO:1, SEQ ID NO:4, SEQ ID NO:7 or SEQ ID NO:454.
Light chain variable region CDR1 may include the amino acid sequence of any of SEQ ID NO:273 to SEQ ID NO:329. Light chain variable region CDR2 may include the amino acid sequence of any of SEQ ID NO:330 to SEQ ID NO:390.Light chain variable Area CDR3 may include the amino acid sequence of any of SEQ ID NO:391 to SEQ ID NO:452.Light chain variable region CDR1, The appropriate combination of CDR2 and CDR3 structural domain is shown in Figure 44 A to Figure 44 C.Comprising such light chain variable region CDR1, CDR2 or The antibody of CDR3 structural domain, or include the combination of light chain variable region CDR1, CDR2 and CDR3 shown in Figure 44 A to Figure 44 C Antibody also may include heavy chain variable region.Heavy chain variable region may include SEQ ID NO:1, SEQ ID NO:4, SEQ ID NO:7 or The amino acid sequence of SEQ ID NO:454.
In some respects, IL-15 (such as human IL-15 compound with IL-15R α) is combined to antibody specificity, and includes The weight of the heavy chain variable region CDR1 of amino acid sequence containing SEQ ID NO:16, amino acid sequence containing SEQ ID NO:17 Chain variable region CDR2, amino acid sequence containing SEQ ID NO:20 heavy chain variable region CDR3, contain SEQ ID NO:25's The light chain variable region CDR1 of amino acid sequence, amino acid sequence containing SEQ ID NO:28 light chain variable region CDR2 and contain The light chain variable region CDR3 of the amino acid sequence of SEQ ID NO:29.Antibody also may include containing SEQ ID NO:12, SEQ ID The heavy chain variable region FR3 of the amino acid sequence of NO:13 or SEQ ID NO:14.
Antibody includes the heavy chain variable region of the amino acid sequence containing SEQ ID NO:16 in some preferred aspects, CDR1, the heavy chain variable region CDR2 of amino acid sequence containing SEQ ID NO:18, the amino acid sequence containing SEQ ID NO:20 The heavy chain variable region CDR3 of column, amino acid sequence containing SEQ ID NO:26 light chain variable region CDR1, contain SEQ ID The light chain variable region of the light chain variable region CDR2 of the amino acid sequence of NO:28 and the amino acid sequence containing SEQ ID NO:30 CDR3.Antibody also may include the heavy chain variable region FR3 of the amino acid sequence containing SEQ ID NO:12 or SEQ ID NO:13.
In some respects, IL-15 (such as human IL-15 compound with IL-15R α) is combined to antibody specificity, and includes The weight of the heavy chain variable region CDR1 of amino acid sequence containing SEQ ID NO:16, amino acid sequence containing SEQ ID NO:19 Chain variable region CDR2, amino acid sequence containing SEQ ID NO:20 heavy chain variable region CDR3, contain SEQ ID NO:27's The light chain variable region CDR1 of amino acid sequence, amino acid sequence containing SEQ ID NO:28 light chain variable region CDR2 and contain The light chain variable region CDR3 of the amino acid sequence of SEQ ID NO:31.Antibody also may include containing SEQ ID NO:12, SEQ ID The heavy chain variable region FR3 of the amino acid sequence of NO:13 or SEQ ID NO:14.
In some respects, IL-15 (such as human IL-15 compound with IL-15R α) is combined to antibody specificity, and includes The weight of the heavy chain variable region CDR1 of amino acid sequence containing SEQ ID NO:16, amino acid sequence containing SEQ ID NO:18 Chain variable region CDR2, amino acid sequence containing SEQ ID NO:20 heavy chain variable region CDR3, contain SEQ ID NO:27's The light chain variable region CDR1 of amino acid sequence, amino acid sequence containing SEQ ID NO:28 light chain variable region CDR2 and contain The light chain variable region CDR3 of the amino acid sequence of SEQ ID NO:31.Antibody also may include containing SEQ ID NO:12 or SEQ ID The heavy chain variable region FR3 of the amino acid sequence of NO:14.
In some respects, IL-15 (such as human IL-15 compound with IL-15R α) is combined to antibody specificity, and includes The weight of the heavy chain variable region CDR1 of amino acid sequence containing SEQ ID NO:16, amino acid sequence containing SEQ ID NO:18 Chain variable region CDR2, amino acid sequence containing SEQ ID NO:20 heavy chain variable region CDR3, contain SEQ ID NO:26's The light chain variable region CDR1 of amino acid sequence, amino acid sequence containing SEQ ID NO:28 light chain variable region CDR2 and contain The light chain variable region CDR3 of the amino acid sequence of SEQ ID NO:31.Antibody also may include containing SEQ ID NO:12 or SEQ ID The heavy chain variable region FR3 of the amino acid sequence of NO:13.
In some respects, IL-15 (such as human IL-15 compound with IL-15R α) is combined to antibody specificity, and includes The weight of the heavy chain variable region CDR1 of amino acid sequence containing SEQ ID NO:16, amino acid sequence containing SEQ ID NO:18 Chain variable region CDR2, amino acid sequence containing SEQ ID NO:20 heavy chain variable region CDR3, contain SEQ ID NO:27's The light chain variable region CDR1 of amino acid sequence, amino acid sequence containing SEQ ID NO:28 light chain variable region CDR2 and contain The light chain variable region CDR3 of the amino acid sequence of SEQ ID NO:30.Antibody also may include containing SEQ ID NO:12 or SEQ ID The heavy chain variable region FR3 of the amino acid sequence of NO:13.
In some respects, IL-15 (such as human IL-15 compound with IL-15R α) is combined to antibody specificity, and includes The weight of the heavy chain variable region CDR1 of amino acid sequence containing SEQ ID NO:16, amino acid sequence containing SEQ ID NO:18 Chain variable region CDR2, amino acid sequence containing SEQ ID NO:20 heavy chain variable region CDR3, contain SEQ ID NO:27's The light chain variable region CDR1 of amino acid sequence, amino acid sequence containing SEQ ID NO:28 light chain variable region CDR2 and contain The light chain variable region CDR3 of the amino acid sequence of SEQ ID NO:29, wherein the Xaa5 of SEQ ID NO:29 be F (SEQ ID NO: 519).Antibody also may include the heavy chain variable region FR3 of the amino acid sequence containing SEQ ID NO:12 or SEQ ID NO:13.
In some respects, IL-15 (such as human IL-15 compound with IL-15R α) is combined to antibody specificity, and wrapped Contain: heavy chain variable region, it includes the CDR2 of the amino acid sequence containing SEQ ID NO:18；With light chain variable region or light chain.Gently Chain variable region may include SEQ ID NO:2, SEQ ID NO:5, SEQ ID NO:8, SEQ ID NO:455, SEQ ID NO:457 Or the amino acid sequence of SEQ ID NO:459.Light chain variable region may include SEQ ID NO:503, SEQ ID NO:505, SEQ The amino acid sequence of ID NO:506, SEQ ID NO:507, SEQ ID NO:509 or SEQ ID NO:510.Light chain may include The amino acid sequence of SEQ ID NO:6, SEQ ID NO:9, SEQ ID NO:456, SEQ ID NO:458 or SEQ ID NO:460 Column.
Antibody may specifically bind IL-15 (such as human IL-15 compound with IL-15R α), and includes or also include Heavy chain variable region, it includes the subdomains containing amino acid sequence shown in following table:
Antibody may specifically bind IL-15 (such as human IL-15 compound with IL-15R α), and includes or also include Light chain variable region, it includes the subdomains containing amino acid sequence shown in following table:
In some respects, IL-15 (such as human IL-15 compound with IL-15R α) is combined to antibody specificity, and includes The heavy chain variable region of amino acid sequence containing SEQ ID NO:1.Antibody includes to contain SEQ ID in some preferred aspects, The heavy chain variable region of the amino acid sequence of NO:4.Antibody includes the amino acid containing SEQ ID NO:7 in some preferred aspects, The heavy chain variable region of sequence.Antibody includes the heavy chain of the amino acid sequence containing SEQ ID NO:454 in some preferred aspects, Variable region.Antibody also may include light chain variable region or light chain.Light chain variable region may include SEQ ID NO:2, SEQ ID NO:5, The amino acid sequence of SEQ ID NO:8, SEQ ID NO:454, SEQ ID NO:457 or SEQ ID NO:459.Light chain variable region May include SEQ ID NO:503, SEQ ID NO:505, SEQ ID NO:506, SEQ ID NO:507, SEQ ID NO:509 or The amino acid sequence of SEQ ID NO:510.Light chain may include SEQ ID NO:3, SEQ ID NO:6, SEQ ID NO:9, SEQ The amino acid sequence of ID NO:456, SEQ ID NO:458 or SEQ ID NO:460.
In some respects, IL-15 (such as human IL-15 compound with IL-15R α) is combined to antibody specificity, and includes The light chain variable region of amino acid sequence containing SEQ ID NO:2.Antibody includes to contain SEQ ID in some preferred aspects, The light chain variable region of the amino acid sequence of NO:5.Antibody includes the amino acid containing SEQ ID NO:8 in some preferred aspects, The light chain variable region of sequence.Antibody includes the light chain of the amino acid sequence containing SEQ ID NO:455 in some preferred aspects, Variable region.Antibody includes the light chain variable region of the amino acid sequence containing SEQ ID NO:457 in some preferred aspects,.? Some preferred aspects, antibody include the light chain variable region of the amino acid sequence containing SEQ ID NO:459.Some preferred Aspect, antibody include the light chain variable region of the amino acid sequence containing SEQ ID NO:503.Antibody in some preferred aspects, Light chain variable region comprising the amino acid sequence containing SEQ ID NO:505.Antibody contains in some preferred aspects, The light chain variable region of the amino acid sequence of SEQ ID NO:506.Antibody includes to contain SEQ ID NO in some preferred aspects: The light chain variable region of 507 amino acid sequence.Antibody includes the amino containing SEQ ID NO:509 in some preferred aspects, The light chain variable region of acid sequence.Antibody includes the light of the amino acid sequence containing SEQ ID NO:510 in some preferred aspects, Chain variable region.Antibody also may include heavy chain variable region.Heavy chain variable region may include SEQ ID NO:1, SEQ ID NO:4, SEQ The amino acid sequence of ID NO:7 or SEQ ID NO:454.
In some respects, IL-15 (such as human IL-15 compound with IL-15R α) is combined to antibody specificity, and includes The light chain of amino acid sequence containing SEQ ID NO:3.Antibody includes to contain SEQ ID NO:6's in some preferred aspects, The light chain of amino acid sequence.Antibody includes the light chain of the amino acid sequence containing SEQ ID NO:9 in some preferred aspects,. Antibody includes the light chain of the amino acid sequence containing SEQ ID NO:456 in some preferred aspects,.In some preferred sides Face, antibody include the light chain of the amino acid sequence containing SEQ ID NO:458.Antibody contains in some preferred aspects, The light chain of the amino acid sequence of SEQ ID NO:460.Antibody also may include heavy chain variable region.Heavy chain variable region may include SEQ ID The amino acid sequence of NO:1, SEQ ID NO:4, SEQ ID NO:7 or SEQ ID NO:454.
Antibody includes the heavy chain variable region of the amino acid sequence containing SEQ ID NO:1 and the ammonia containing SEQ ID NO:2 The light chain variable region of base acid sequence.Antibody includes the heavy chain variable region of the amino acid sequence containing SEQ ID NO:1 and contains SEQ The light chain variable region of the amino acid sequence of ID NO:5.Antibody includes the weight chain variable of the amino acid sequence containing SEQ ID NO:1 The light chain variable region in area and the amino acid sequence containing SEQ ID NO:8.Antibody includes the amino acid sequence containing SEQ ID NO:1 The light chain variable region of the heavy chain variable region of column and the amino acid sequence containing SEQ ID NO:455.Antibody includes to contain SEQ ID The light chain variable region of the heavy chain variable region of the amino acid sequence of NO:1 and the amino acid sequence containing SEQ ID NO:457.Antibody Heavy chain variable region comprising the amino acid sequence containing SEQ ID NO:1 and the amino acid sequence containing SEQ ID NO:459 Light chain variable region.Antibody comprising such heavy chain variable region and light chain variable region pair preferably specifically combine IL-15 (such as The compound human IL-15 with IL-15R α).
Antibody includes the heavy chain variable region of the amino acid sequence containing SEQ ID NO:4 and the ammonia containing SEQ ID NO:2 The light chain variable region of base acid sequence.Antibody includes the heavy chain variable region of the amino acid sequence containing SEQ ID NO:4 and contains SEQ The light chain variable region of the amino acid sequence of ID NO:5.Antibody includes the weight chain variable of the amino acid sequence containing SEQ ID NO:4 The light chain variable region in area and the amino acid sequence containing SEQ ID NO:8.Antibody includes the amino acid sequence containing SEQ ID NO:4 The light chain variable region of the heavy chain variable region of column and the amino acid sequence containing SEQ ID NO:455.Antibody includes to contain SEQ ID The light chain variable region of the heavy chain variable region of the amino acid sequence of NO:4 and the amino acid sequence containing SEQ ID NO:457.Antibody Heavy chain variable region comprising the amino acid sequence containing SEQ ID NO:4 and the amino acid sequence containing SEQID NO:459 it is light Chain variable region.Antibody includes the heavy chain variable region of the amino acid sequence containing SEQ ID NO:4 and contains SEQ ID NO:503's The light chain variable region of amino acid sequence.Antibody includes the heavy chain variable region of the amino acid sequence containing SEQ ID NO:4 and contains The light chain variable region of the amino acid sequence of SEQ ID NO:505.Antibody includes the weight of the amino acid sequence containing SEQ ID NO:4 The light chain variable region of chain variable region and the amino acid sequence containing SEQ ID NO:507.Antibody includes to contain SEQ ID NO:4's The light chain variable region of the heavy chain variable region of amino acid sequence and the amino acid sequence containing SEQ ID NO:509.Antibody contains The light chain of the heavy chain variable region and the amino acid sequence containing SEQ ID NO:510 that have the amino acid sequence of SEQ ID NO:4 can Become area.Antibody includes the heavy chain variable region of the amino acid sequence containing SEQ ID NO:454 and the amino containing SEQ ID NO:8 The light chain variable region of acid sequence.Antibody includes the heavy chain variable region of the amino acid sequence containing SEQ ID NO:454 and contains SEQ The light chain variable region of the amino acid sequence of ID NO:455.Antibody includes the heavy chain of the amino acid sequence containing SEQ ID NO:454 The light chain variable region of variable region and the amino acid sequence containing SEQID NO:503.Antibody includes to contain SEQ ID NO:454's The light chain variable region of the heavy chain variable region of amino acid sequence and the amino acid sequence containing SEQ ID NO:457.Antibody contains There are the heavy chain variable region of the amino acid sequence of SEQ ID NO:454 and the light chain of the amino acid sequence containing SEQ ID NO:505 Variable region.Antibody includes the heavy chain variable region of the amino acid sequence containing SEQ ID NO:454 and contains SEQ ID NO:506's The light chain variable region of amino acid sequence.Antibody includes the heavy chain variable region of the amino acid sequence containing SEQ ID NO:454 and contains There is the light chain variable region of the amino acid sequence of SEQ ID NO:507.Antibody includes the amino acid sequence containing SEQ ID NO:454 Heavy chain variable region and the amino acid sequence containing SEQ ID NO:5 light chain variable region.Antibody includes to contain SEQ ID NO: The light chain variable region of the heavy chain variable region of 454 amino acid sequence and the amino acid sequence containing SEQ ID NO:509.Antibody packet Heavy chain variable region containing the amino acid sequence containing SEQ ID NO:454 and the amino acid sequence containing SEQ ID NO:510 Light chain variable region.Antibody includes the heavy chain variable region of the amino acid sequence containing SEQ ID NO:7 and contains SEQ ID NO:8's The light chain variable region of amino acid sequence.Antibody comprising such heavy chain variable region and light chain variable region pair is preferably specifically tied It closes IL-15 (such as human IL-15 compound with IL-15R α).
Antibody includes the heavy chain variable region of the amino acid sequence containing SEQ ID NO:1 and the ammonia containing SEQ ID NO:3 The light chain of base acid sequence.Antibody include the amino acid sequence containing SEQ ID NO:1 heavy chain variable region and contain SEQ ID The light chain of the amino acid sequence of NO:6.Antibody includes the heavy chain variable region of the amino acid sequence containing SEQ ID NO:1 and contains The light chain of the amino acid sequence of SEQ ID NO:9.Antibody includes the heavy chain variable region of the amino acid sequence containing SEQ ID NO:1 With the light chain of the amino acid sequence containing SEQ ID NO:456.Antibody includes the weight of the amino acid sequence containing SEQ ID NO:1 The light chain of chain variable region and the amino acid sequence containing SEQ ID NO:458.Antibody includes the amino acid containing SEQ ID NO:1 The light chain of the heavy chain variable region of sequence and the amino acid sequence containing SEQ ID NO:460.Comprising such heavy chain variable region and gently The antibody of chain pair preferably specifically combines IL-15 (such as human IL-15 compound with IL-15R α).
Antibody includes the heavy chain variable region of the amino acid sequence containing SEQ ID NO:4 and the ammonia containing SEQ ID NO:3 The light chain of base acid sequence.Antibody include the amino acid sequence containing SEQ ID NO:4 heavy chain variable region and contain SEQ ID The light chain of the amino acid sequence of NO:6.Antibody includes the heavy chain variable region of the amino acid sequence containing SEQ ID NO:4 and contains The light chain of the amino acid sequence of SEQ ID NO:9.Antibody includes the heavy chain variable region of the amino acid sequence containing SEQ ID NO:4 With the light chain of the amino acid sequence containing SEQ ID NO:456.Antibody includes the weight of the amino acid sequence containing SEQ ID NO:4 The light chain of chain variable region and the amino acid sequence containing SEQ ID NO:458.Antibody includes the amino acid containing SEQ ID NO:4 The light chain of the heavy chain variable region of sequence and the amino acid sequence containing SEQ ID NO:460.Antibody includes to contain SEQ ID NO: The light chain of the heavy chain variable region of 454 amino acid sequence and the amino acid sequence containing SEQ ID NO:9.It can comprising such heavy chain The antibody for becoming area and light chain pair preferably specifically combines IL-15 (such as human IL-15 compound with IL-15R α).
In some respects, IL-15 (such as human IL-15 compound with IL-15R α) is combined to antibody specificity, and includes Contain SEQ ID NO:461, SEQ ID NO:462, SEQ ID NO:463, SEQ ID NO:464, SEQ ID NO:465, SEQ ID NO:466, SEQ ID NO:467, SEQ ID NO:468, SEQ ID NO:469, SEQ ID NO:470, SEQ ID NO: 471, SEQ ID NO:472, SEQ ID NO:473, SEQ ID NO:474, SEQ ID NO:475, SEQ ID NO:476, SEQ ID NO:477, SEQ ID NO:478, SEQ ID NO:479, SEQ ID NO:480, SEQ ID NO:481, SEQ ID NO: 482, SEQ ID NO:483, SEQ ID NO:484, SEQ ID NO:485, SEQ ID NO:486, SEQ ID NO:487, SEQ The heavy chain variable region of the amino acid sequence of any of ID NO:488, SEQ ID NO:489 or SEQ ID NO:490, and it is light Chain variable region or light chain.In some respects, IL-15 (such as human IL-15 compound with IL-15R α) is combined to antibody specificity, It and include containing SEQ ID NO:461, SEQ ID NO:462, SEQ ID NO:463, SEQ ID NO:464, SEQ ID NO:465, SEQ ID NO:466, SEQ ID NO:467, SEQ ID NO:468, SEQ ID NO:469, SEQ ID NO:470, SEQ ID NO:471, SEQ ID NO:472, SEQ ID NO:473, SEQ ID NO:474, SEQ ID NO:475, SEQ ID NO:476, SEQ ID NO:477, SEQ ID NO:478, SEQ ID NO:479, SEQ ID NO:480, SEQ ID NO:481, SEQ ID NO:482, SEQ ID NO:483, SEQ ID NO:484, SEQ ID NO:485, SEQ ID NO:486, SEQ ID The heavy chain of the amino acid sequence of any of NO:487, SEQ ID NO:488, SEQ ID NO:489 or SEQ ID NO:490 can Become area and light chain variable region or light chain, and the light chain variable region can be SEQ ID NO:491, SEQ ID NO: 492, SEQ ID NO:493, SEQ ID NO:494, SEQ ID NO:495, SEQ ID NO:496, SEQ ID NO:497, SEQ Any of ID NO:498 or SEQ ID NO:499.In some respects, antibody specificity combine IL-15 (such as with IL- 15R α compound human IL-15), and include containing SEQ ID NO:491, SEQ ID NO:492, SEQ ID NO:493, SEQ ID NO:494, SEQ ID NO:495, SEQ ID NO:496, SEQ ID NO:497, SEQ ID NO:498 or SEQ ID NO: The light chain variable region and heavy chain variable region of any of 499 amino acid sequence.Include such heavy chain variable region and light chain pair Antibody preferably specifically combine IL-15 (such as human IL-15 compound with IL-15R α).
In some respects, IL-15 (such as human IL-15 compound with IL-15R α) is combined to antibody specificity, and includes The heavy chain variable region of amino acid sequence containing any of SEQ ID NO:7, SEQ ID NO:454 and SEQ ID NO:4, with And light chain variable region or light chain.In some respects, IL-15 (such as the people IL- compound with IL-15R α is combined to antibody specificity It 15), and include the amino acid sequence containing any of SEQ ID NO:7, SEQ ID NO:454 and SEQ ID NO:4 Heavy chain variable region and light chain variable region or light chain, and the light chain variable region can be SEQ ID NO:5, SEQ ID NO:8, SEQ ID NO:455, SEQ ID NO:457, SEQ ID NO:459, SEQ ID NO:503, SEQ ID NO:505, Any of SEQ ID NO:506, SEQ ID NO:507, SEQ ID NO:509 or SEQ ID NO:510.In some sides Face, antibody specificity combine IL-15 (such as human IL-15 compound with IL-15R α), and include containing SEQ ID NO:5, SEQ ID NO:8, SEQ ID NO:455, SEQ ID NO:457, SEQ ID NO:459, SEQ ID NO:503, SEQ ID The ammonia of any of NO:505, SEQ ID NO:506, SEQ ID NO:507, SEQ ID NO:509 or SEQ ID NO:510 The light chain variable region and heavy chain variable region of base acid sequence.
Antibody may specifically bind IL-15 (such as human IL-15 compound with IL-15R α), and include containing following table Shown in amino acid sequence VH and VL or light chain pair:
Antibody may specifically bind IL-15 (such as human IL-15 compound with IL-15R α), and include containing following table Shown in amino acid sequence VH and VL or light chain pair:
Any antibody combination IL-15 for being described herein or illustrating, is preferably human IL-15.Antibody can combine not compound IL-15 or the IL-15-IL-15 compound compound with IL-15 receptor alpha (IL-15R- α or IL-15R α).In some respects, people IL-15 includes the amino acid sequence of SEQ ID NO:511.In some respects, IL-15R- α includes the amino of SEQ ID NO:512 Acid sequence, without AVI and His label.In some respects, IL-15R- α includes the amino acid sequence of SEQ ID NO:520.
Antibody can have affinity, dissociation constant (KD) to IL-15 (such as human IL-15 compound with IL-15R α) Less than about 1x10-2M.In some embodiments, KD is less than about 1x10-3M.In other embodiments, KD is less than about 1x10- 4M.In some embodiments, KD is less than about 1x10-5M.In other embodiments, KD is less than about 1x10-6M.In other implementations In scheme, KD is less than about 1x10-7M.In other embodiments, KD is less than about 1x10-8M.In other embodiments, KD is small In about 1x10-9M.In other embodiments, KD is less than about 1x10-10M.In other embodiments, KD is less than about 1x10-11M。 In some embodiments, KD is less than about 1x10-12M.In other embodiments, KD is less than about 1x10-13M.In other implementations In scheme, KD is less than about 1x10-14M.In other embodiments, KD is less than about 1x10-15M.In some respects, KD is less than about 1.8x10-9M.In some respects, KD is about 1.2x10-10M to about 2x10-10M.In some respects, KD is about 1.3x10-10M is to about 1.9x10-10M.In some respects, KD is about 1.33x10-10M to about 1.93x10-10M.In some respects, KD is about 1.6x10- 10M to about 1.8x10-10M.In some respects, KD is about 1.7x10-10M.Affine force value refers to the value obtained by standard method, The standard method includes surface plasmon resonance (SPR), such asAnalysis uses Red 96 (Forte Bio) impregnate the analysis that reading system (Dip-and-Read system) is carried out.In preferred embodiments, Dissociation constant is measured by SPR.
GeneralIn SPR analysis, antibody is fixed in sensor chip surface, and will be suitable dense The IL-15 or IL-15 and IL-15 receptor alpha compound of degree pass through surface.The variation of refractive index is detected, and is passed using Software Create Figure is felt for analysis.When interaction between immobilized antibody and IL-15 or IL-15 compound can carry out any suitable Between length, including about 1 to about 2 minute.The temperature of interaction can be any suitable temperature, including about 25 DEG C.
It can be monoclonal antibody in conjunction with the antibody of IL-15 (such as human IL-15 compound with IL-15R α).Preferably, resist Body is the full length antibody comprising heavy chain and light chain.In some respects, antibody includes to remain overall length parent antibody molecule in antibody (for example, for IL-15) antigen-binding specificity and preferably substantially remain its affinity derivative or Segment or part.For example, derivative may include single variable region (heavy chain variable region or light chain variable region).Suitable antibody is derivative Other of object and segment example include but is not limited to the antibody with multi-epitope specificity, double antibody, miniantibody, FAb, F (Ab ') 2, Fd, Fabc and Fv molecule, single-stranded (Sc) antibody, single-chain Fv antibody (scFv), single antibody light chain, single antibody heavy chain, anti- Fusions, heavy chain monomer or dimer, light chain monomers or dimer between body chain and other molecules, by a heavy chain and one The dimer and other polymers of light chain composition.Single-chain Fv antibody can be multivalence.Antibody derivatives, segment and/or portion Recombination can be passed through by, which dividing, generates and is expressed by any cell type (prokaryotic cell or eukaryocyte).
In full length antibody, each heavy chain is by heavy chain variable region (abbreviated herein as HCVR or VH) and light chain constant district's groups At.Heavy chain constant region is made of three domain Cs H1, CH2 and CH3.Every light chain by light chain variable region (abbreviated herein as LCVR or VL) and constant region of light chain composition.Constant region of light chain is made of a domain C L.The area VH and the area VL can be further thin It is divided into hypervariable region, referred to as complementary determining region (CDR), interleaves more conservative region, referred to as framework region (FR).Each VH and VL are by three A CDR and four FR composition, they are arranged from amino terminal to carboxyl terminal in the following order: FRI, CDR1, FR2, CDR2, FR3,CDR3,FR4.In general, changing compared to CDR sequence, FR sequence variation is less likely the antigenic binding property of interference antibody.Exempt from Epidemic disease globulin molecule can be any type (such as IgG, IgE, IgM, IgD, IgA and IgY), classification (such as IgG1, IgG2, IgG3, IgG4, IgA1 and IgA2) or subclass.
Anti- IL-15 antibody is preferably complete people.Fully human antibodies are that entire molecule is people or is otherwise source of people Antibody, or include amino acid sequence identical with the person form of antibody.Fully human antibodies include obtaining from people's V gene library Antibody, for example, wherein the people's gene of encoding antibody variable is to pass through recombinant expression.Fully human antibodies can be in other biological (such as mouse and xenotypic mice technology (xenomouse technology)) is expressed in body or is using by oneself encoding human antibody's It is expressed in the cell of the other organisms of genetic transformation.According to WO 08/151081, fully human antibodies can beExpression in rat system (OMT, Inc.).However, fully human antibodies may include not by naturally occurring people's sequence The amino acid residue for arranging coding, for example including the mutation by random mutation or rite-directed mutagenesis introducing.
In some respects, anti-IL-15 antibody may include the albumen frame from non-immunoglobulin.For example, can refer to (Ku et al. (1995) Proc.Natl.Acad.Sci.USA 92:6552-6556), which depict tool there are two ring be randomized with Four-helix bundle the protein cytochrome b562, the CDR for generating CDR have been selected for antigen binding.
Anti- IL-15 antibody may include posttranslational modification or part, and the posttranslational modification or part can influence antibody Activity, circulating half-life or storage/storage stability.For example, antibody can be methylation, acetylation, glycosylated, sulphur It is acidification, phosphorylation, carboxylation and/or amidated, or may include other suitable portions well-known in the art Point.Part include be typically found in circulation in immunoglobulin molecules on or by recombinant expression system (including protokaryon and Eukaryotic expression system) otherwise it is added to the combination of any chemical group or group in antibody.
The disclosure imagine side chain modification example include such as carry out in the following manner it is amido modified: by with aldehyde Reaction then restores the standard reductive alkylation carried out with NaBH4；With methyl vinyl imidic acid (methylacetimidate) amidino groups Change；Use acetic anhydride acylation；With cyanate by amino carbamylation；With 2,4,6- trinitrobenzene sulfonic acid (TNBS) by amino trinitro- Henzylate；With succinic anhydride and tetrabydrophthalic anhydride by aminoacylates；And with pyridoxal 5-phosphate by lysine pyridoxal Change (pyridoxylation), is then restored with NaBH4.
The guanidine radicals of arginine residues can be miscellaneous by being formed with the reagent of such as 2,3- diacetyl, phenylglyoxal and glyoxal Cyclic condensation product is modified.Carboxyl can make carbodiimide activation by forming O- acyl isourea, and subsequent derivatization becomes for example Corresponding amide is modified.The method of modifying of sulfydryl may be, for example, with iodoacetic acid or iodoacetamide carboxy methylation；Performic acid oxygen It is melted into cysteic acid；Mixed disulfide is formed with other mercaptan compounds；With maleimide, maleic anhydride or other take The maleimide in generation reacts；Use 4- chloromercuri-benzoate, 4- chloromercuribenzene sulfonate, phenylmercuric chloride, 2- chlorine mercury -4- nitrophenol Mercury derivatives are formed with other mercurial；Cyanate carbamylation is used under alkaline ph value.Trp residue can for example, by with N-bromosuccinimide oxidation, or modified indoles cycloalkylation with 2- hydroxyl -5- nitrobenzyl bromide or sulfenyl halogen.? On the other hand, tyrosine residue can form 3- nitrotyrosine derivative and change by being nitrified with tetranitromethane.Histidine The modification of the imidazole ring of residue can be by completing with iodoacetic acid derivatives alkylation or with pyrocarbonic acid diethyl ester N- carbethoxylation.
Anti- IL-15 antibody may include the modification for adjusting serum half-life and bio distribution, including but not limited to adjusting antibody With the modification of neonatal Fc receptor (FcRn) interaction, FcRn is that one kind is protecting IgG from catabolism and maintaining high blood The receptor to play a crucial role in clear antibody concentration.Such as United States Patent (USP) No.7, described in 083,784, in IgG1, IgG2 or IgG4 The area Fc may occur to adjust the modification of serum half-life, including (number is according to EU numbering system by M252Y/S254T/T256E (Edelman, GM et al. (1969) Proc.Natl.Acad.USA63:78-85)) triple substitutions.Other substitutions can be the 250 and the 428th generations, see, for example, United States Patent (USP) No 7,217,797；And at the 307th, the 380th and the 434th Position occurs, see, for example, PCT Publication No.WO 00/042072.Adjust Fc receptor combine and it is receptor-mediated subsequent by these The example that the constant domain amino-acid of function (including FcRn combination and serum half-life) replaces is described in the U.S. and announces In No.2009/0142340,2009/0068175 and 2009/0092599.The antibody of any classification can be omitted or remove heavy chain C-terminal lysine is to reduce heterogeneous (Δ K).The substitution of S228P (EU number) can stablize internal antibody Fab arm in human IgG 4 Exchange (Labrin et al. (2009) Nature Biotechnol.27:8；767-773), which can be with M252Y/S254T/ T256E and/or Δ K modification exists simultaneously.
Anti- IL-15 antibody preferably comprises people's constant domain.Heavy chain constant domain is preferably human IgG1, IgG2 or IgG4 Constant domain.Light chain constant domain is preferably people's λ constant domain.
The people heavy chain IgG1 constant region that can be used for anti-IL-15 antibody can be selected from human IgG1 (SEQ ID NO:32), people IgG1 (Δ K) (SEQ ID NO:33), human IgG1 252Y/254T/256E (SEQ ID NO:34), human IgG1 252Y/254T/ 256E (Δ K) (SEQ ID NO:35), human IgG1 L235A/G237A (SEQ ID NO:36), human IgG1 L235A/G237A (Δ K) (SEQ ID NO:37), human IgG1 L234A/L235A/G237A (SEQ ID NO:38) and human IgG1 L234A/ L235A/G237A (Δ K) (SEQ ID NO:39).The people's heavy chain IgG2 constant region that can be used for anti-IL-15 antibody can be selected from Human IgG2 (SEQ ID NO:40), human IgG2 (Δ K) (SEQ ID NO:41), human IgG2 A330S/P331S (SEQ ID NO: And human IgG (Δ K) (SEQ ID NO:43) 42).The people heavy chain IgG4 constant region that can be used for anti-IL-15 antibody can be selected from people IgG4 (SEQ ID NO:44), human IgG 4 (Δ K) (SEQ ID NO:45), human IgG 4S228P (SEQ ID NO:46), people IgG4S228P (Δ K) (SEQ ID NO:47), human IgG 4228P/252Y/254T/256E (SEQ ID NO:48), people IgG4228P/252Y/254T/256E (Δ K) (SEQ ID NO:49), human IgG 4252Y/254T/256E (SEQ ID NO:50) With human IgG 4252Y/254T/256E (Δ K) (SEQ ID NO:51).
Anti- IL-15 antibody can mark, in conjunction with or be conjugated to any chemistry or biomolecular moieties.Labelled antibody can be used for Treatment, diagnosis or basic research application.Such label/conjugate can be detectable, such as fluorescent dye, electrochemical luminescence Probe, quantum dot, radioactive label, enzyme, fluorescin and luminescent protein, or may include biotin or PEG.
Antibody can be by known protection/blocking groups derivatization, to prevent proteolytic cleavage or enhancing active or steady It is qualitative.
The disclosure characterizes the polynucleotide sequence, its structural domain (such as VH and VL) and its Asia for encoding anti-IL-15 antibody Structural domain base (such as FR and CDR).Polynucleotides include but is not limited to the heterozygote of RNA, DNA, cDNA, RNA and DNA, and RNA, DNA or the single-stranded of its heterozygote, double-strand or three chains.Complementary nucleic acid sequences are also within the scope of the present disclosure.
In some respects, polynucleotides include the first nucleic acid sequence of encoding antibody heavy variable region, the weight chain variable Area includes the amino acid sequence of SEQ ID NO:1, SEQ ID NO:4 or SEQ ID NO:7.Polynucleotides also may include that coding is anti- The second nucleotide sequence of body light chain variable region, the light chain variable region include SEQ ID NO:2, SEQ ID NO:5 or SEQ ID The amino acid sequence of NO:8.Polynucleotides also may include the second nucleotide sequence of encoding antibody light, and the light chain includes SEQ The amino acid sequence of ID NO:3, SEQ ID NO:6 or SEQ ID NO:9.Polynucleotides also may include that encoding antibody heavy is constant The third nucleic acid sequence in area, any of described all IgG1, IgG2 or IgG4 constant regions as described herein of heavy chain constant region.
In some respects, polynucleotides include the first nucleic acid sequence of encoding antibody heavy variable region, the weight chain variable Area includes the amino acid sequence of SEQ ID NO:4, SEQ ID NO:7 or SEQ ID NO:454.Polynucleotides also may include coding The second nucleotide sequence of antibody's light chain variable region, the light chain variable region include SEQ ID NO:5, SEQ ID NO:8, SEQ ID NO:455, SEQ ID NO:457, SEQ ID NO:459, SEQ ID NO:503, SEQ ID NO:505, SEQ ID NO:506, The amino acid sequence of SEQ ID NO:507, SEQ ID NO:509 or SEQ ID NO:510.Polynucleotides also may include that coding is anti- The second nucleotide sequence of body light chain, the light chain include SEQ ID NO:6, SEQ ID NO:9, SEQ ID NO:456, SEQ ID The amino acid sequence of NO:458 or SEQ ID NO:460.Polynucleotides also may include the third core of encoding antibody heavy constant region Acid sequence, any of described all IgG1, IgG2 or IgG4 constant regions as described herein of heavy chain constant region.
In some respects, polynucleotides include the first nucleic acid sequence of encoding antibody light variable region, the light chain variable Area includes the amino acid sequence of SEQ ID NO:2, SEQ ID NO:5 or SEQ ID NO:8.In some respects, polynucleotides packet The first nucleic acid sequence containing encoding antibody light, the light chain include SEQ ID NO:3, SEQ ID NO:6 or SEQ ID NO:9 Amino acid sequence.In some respects, polynucleotides include the nucleic acid sequence of SEQ ID NO:517.In some respects, multicore glycosides Acid includes the nucleic acid sequence of SEQ ID NO:518.
In some respects, polynucleotides include the first nucleic acid sequence of encoding antibody light variable region, the light chain variable Area includes SEQ ID NO:5, SEQ ID NO:8, SEQ ID NO:455, SEQ ID NO:457, SEQ ID NO:459, SEQ ID NO:503, SEQ ID NO:505, SEQ ID NO:506, SEQ ID NO:507, SEQ ID NO:509 or SEQ ID NO: 510 amino acid sequence.In some respects, polynucleotides include the first nucleic acid sequence of encoding antibody light, the light chain packet The amino acid of ID containing SEQ NO:6, SEQ ID NO:9, SEQ ID NO:456, SEQ ID NO:458 or SEQ ID NO:460 Sequence.
Any such polynucleotides may include in carrier.Therefore it provides the carrier comprising polynucleotides is as the disclosure A part.Carrier can be expression vector.Thus provide the recombinant expression carrier of the sequence containing encoding target polypeptide.Table Contain one or more other sequences, such as, but not limited to regulating and controlling sequence, selectable marker, purification tag or poly- up to carrier Polyadenylation signal.Such controlling element may include transcripting promoter, enhancer, mRNA ribosome bind site or control transcription With the sequence of translation termination.
Expression vector, especially mammalian expression vector, it may include one or more non-transcribed elements such as replicate Point, with the suitable promoter of gene linkage to be expressed and enhancer, other 5 ' or 3 ' flanking non-transcribed sequences, 5 ' or 3 ' untranslateds Sequence (such as required ribosome bind site), site of polyadenylation, donor splicing site and acceptor site or tanscription termination sequence Column.The replication orgin for assigning the ability replicated in specific host can also be merged.
Carrier can be used for converting any one of a variety of host cells well known to those skilled in the art, be preferably able to express The host cell of antibody.Carrier includes but is not limited to plasmid, phasmid, clay, rod granule, bacterial artificial chromosome (BAC), yeast Artificial chromosome (YAC) and baculoviral and other bacteriums, eukaryon, yeast and viral vectors.Suitable host cell includes But Chinese hamster ovary celI, NS0 cell, HEK293 cell or eukaryon stable cell lines that are any known or generating are not limited to, and are also wrapped Include bacterium, yeast and insect cell.
Antibody can also be generated by hybridoma；The method for generating hybridoma is it is well known in the art that and being in use for a long time 's.
The disclosure also provides the composition comprising anti-IL-15 antibody.Composition may include times for being described herein and/or illustrating What antibody and such as pharmaceutically acceptable carrier of acceptable carrier.Suitable carrier include do not interfere antibody bioactive and It is preferred that any medium nontoxic to application host.Carrier can be aqueous solution.Composition may include being described herein and/or illustrating Any antibody and pharmaceutically acceptable excipient.
Anti- IL-15 antibody can be used for treating autoimmune disease, the autoimmune disease including IL-15 imbalance.It is anti- IL-15 antibody can be used for treating inflammatory disease, the inflammatory disease including IL-15 imbalance.Anti- IL-15 antibody can be used for treating inflammatory Illness, the inflammatory conditions including IL-15 imbalance.In some respects, anti-IL-15 antibody can be used for treating subject chylous diarrhea, Intractable chylous diarrhea, rheumatoid arthritis, psoriasis, inflammatory bowel disease, type 1 diabetes, alopecia areata disease and certain form of cancer Disease such as T cell large granular lymphocyte leukaemia.Therefore, the disclosure characterizes treatment method.
In some respects, treatment method includes applying to the subject for needing to treat the autoimmune disease that IL-15 lacks of proper care With anti-IL-15 antibody or combinations thereof object, so that the autoimmune disease of the subject obtains medical treatment.Anti- IL-15 antibody is excellent Choosing is applied with the amount for effectively treating the autoimmune disease of the IL-15 imbalance of subject.Effective quantity can be for example according to tested Needs or the situation of person and change.It can be administered under the guidance or control of practitioner.
In some respects, treatment method includes applying anti-IL- to the subject for needing to treat the inflammatory disease that IL-15 lacks of proper care 15 antibody or combinations thereof object, so that the inflammatory disease of the subject obtains medical treatment.Anti- IL-15 antibody preferably with effectively treat by The amount application of the inflammatory disease of the IL-15 imbalance of examination person.Effective quantity can for example change according to the needs of subject or situation. It can be administered under the guidance or control of practitioner.
In some respects, treatment method includes applying anti-IL- to the subject for needing to treat the inflammatory conditions that IL-15 lacks of proper care 15 antibody or combinations thereof object, so that the inflammatory conditions of the subject obtain medical treatment.Anti- IL-15 antibody preferably with effectively treat by The amount application of the inflammatory conditions of the IL-15 imbalance of examination person.Effective quantity can for example change according to the needs of subject or situation. It can be administered under the guidance or control of practitioner.
In some respects, treatment method includes applying anti-IL-15 antibody or its group to the subject for needing to treat chylous diarrhea Close object so that the chylous diarrhea of the subject obtains medical treatment, and chylous diarrhea can be it is intractable.Intractable chylous diarrhea (RCD) involve those after being kept for stringent gluten-free diet 6-12 month and exclude other symptoms reason (including malignant tumour) Fail to cure afterwards and continuous exhibition goes out the patient of chylous diarrhea symptom.Intractable chylous diarrhea may also be before to for a long time without seitan drink Food has response, but (Rishi et al. occurs in the patient for nowadays chylous diarrhea symptom occur after keeping stringent gluten-free diet Expert Review of Gastroenterology&Hepatology:10537-546 (2016)).Anti- IL-15 antibody is preferred Effectively to treat the amount application of the chylous diarrhea of subject.Effective quantity can for example change according to the needs of subject or situation. It can be administered under the guidance or control of practitioner.
Anti- IL-15 antibody can be used for treating or inhibiting one or more symptoms of seitan exposure, such as be drawn by intake seitan The one or more symptoms risen.One or more symptoms include courbature, somatalgia, arthralgia, fatigue, aerogastria, intestines Gas, nausea, colic pain, constipation, diarrhea, fash, headache, migraine, depression and anxiety, brain mist and/or agitation.In general, the method Including applying anti-IL-15 antibody or combinations thereof object to the subject with seitan sensitivity for being exposed to seitan, so that described One or more seitans exposure symptom of subject is inhibited or treats.Anti- IL-15 antibody is preferably effectively to treat or inhibit The amount application of one or more seitans exposure symptom of subject.Effective quantity can for example according to the needs of subject or situation and Variation.It can be administered under the guidance or control of practitioner.
In some respects, treatment method includes applying anti-IL-15 to the subject for needing to treat rheumatoid arthritis to resist Body or combinations thereof object, so that the rheumatoid arthritis of the subject obtains medical treatment.Anti- IL-15 antibody is preferably effectively to treat The amount of the rheumatoid arthritis of subject is applied.Effective quantity can for example change according to the needs of subject or situation.It can It is administered under the guidance or control of practitioner.
In some respects, treatment method includes applying anti-IL-15 antibody or its group to the subject for needing to treat psoriasis Object is closed, so that the psoriasis of the subject obtains medical treatment.The psoriasis of anti-IL-15 antibody preferably effectively to treat subject Amount application.Effective quantity can for example change according to the needs of subject or situation.It can be under the guidance or control of practitioner It is administered.
In some respects, treatment method include applied to the subject for needing to treat inflammatory bowel disease anti-IL-15 antibody or its Composition, so that the inflammatory bowel disease of the subject obtains medical treatment.Inflammatory of the anti-IL-15 antibody preferably effectively to treat subject The amount of enteropathy is applied.Effective quantity can for example change according to the needs of subject or situation.Can practitioner guidance or It is administered under control.
In some respects, treatment method include applied to the subject for needing to treat type 1 diabetes anti-IL-15 antibody or its Composition, so that the type 1 diabetes of the subject obtain medical treatment.1 type of the anti-IL-15 antibody preferably effectively to treat subject The amount of diabetes is applied.Effective quantity can for example change according to the needs of subject or situation.It can be in the guidance of practitioner Or it is administered under control.
In some respects, treatment method includes applying anti-IL-15 antibody or its group to the subject for needing to treat alopecia areata disease Object is closed, so that the alopecia areata disease of the subject obtains medical treatment.The alopecia areata disease of anti-IL-15 antibody preferably effectively to treat subject Amount application.Effective quantity can for example change according to the needs of subject or situation.It can be under the guidance or control of practitioner It is administered.
In some respects, treatment method includes to the subject for needing to treat T cell large granular lymphocyte leukaemia Anti- IL-15 antibody or combinations thereof object is applied, so that the T cell large granular lymphocyte leukaemia of the subject is controlled It treats.Amount application of the anti-IL-15 antibody preferably effectively to treat the T cell large granular lymphocyte leukaemia of subject.Effectively Amount can for example change according to the needs of subject or situation.It can be administered under the guidance or control of practitioner.
Anti- IL-15 antibody can be used for manufacturing drug.For example, anti-IL-15 antibody can be used for manufacturing or preparing for treating cream The drug that gruel is rushed down.Anti- IL-15 antibody can be used for manufacturing or preparing the drug for treating intractable chylous diarrhea.Anti- IL-15 antibody It can be used for manufacturing or preparing the drug for treating rheumatoid arthritis.Anti- IL-15 antibody, which can be used for manufacturing or preparing, to be used for The drug for treating psoriasis.Anti- IL-15 antibody can be used for manufacturing or preparing the drug for treating inflammatory bowel disease.Anti- IL-15 is anti- Body can be used for manufacturing or preparing the drug for treating type 1 diabetes.Anti- IL-15 antibody can be used for manufacturing or preparing for treating The drug of alopecia areata disease.Anti- IL-15 antibody can be used for manufacturing or preparing for treating T cell large granular lymphocyte leukaemia Drug.Anti- IL-15 antibody can be used for manufacturing or preparing to be exposed for treating or inhibiting seitan, such as with seitan sensitivity or allergy Patient in seitan exposure one or more symptoms drug.One or more symptoms may include courbature, body Bitterly, arthralgia, fatigue, aerogastria, intestines gas, nausea, colic pain, constipation, diarrhea, fash, headache, migraine, depression and anxiety, brain Mist and/or agitation.
Anti- IL-15 antibody can be used for treating chylous diarrhea.Anti- IL-15 antibody can be used for treating intractable chylous diarrhea.Anti- IL-15 Antibody can be used for treating rheumatoid arthritis.Anti- IL-15 antibody can be used for treating psoriasis.Anti- IL-15 antibody can be used for controlling Treat inflammatory bowel disease.Anti- IL-15 antibody can be used for treating type 1 diabetes.Anti- IL-15 antibody can be used for treating alopecia areata disease.Anti- IL-15 Antibody can be used for treating T cell large granular lymphocyte leukaemia.Anti- IL-15 antibody can be used for treating or inhibiting seitan sudden and violent One or more symptoms of seitan exposure in dew, such as the patient with seitan sensitivity or allergy.One or more diseases Shape may include courbature, somatalgia, arthralgia, fatigue, aerogastria, intestines gas, nausea, colic pain, constipation, diarrhea, fash, headache, Migraine, depression and anxiety, brain mist and/or agitation.
The disclosure also characterizes the medicine box comprising any anti-IL-15 antibody, these medicine boxs can be used for providing antibody and other For diagnosing, basic research or the agent for the treatment of method etc..In some respects, medicine box is any anti-comprising what is be described herein or illustrate IL-15 antibody and the specification that the antibody is used in the method for treating chylous diarrhea.In some respects, medicine box includes herein Description or any anti-IL-15 antibody illustrated and the explanation that the antibody is used in the method for treating intractable chylous diarrhea Book.In some respects, medicine box includes any anti-IL-15 antibody for being described herein or illustrating and for example suffers from for treating or inhibiting The specification of the antibody is used in the method for there are one or more symptoms of the seitan exposure in the patient of seitan sensitivity or allergy. In some respects, medicine box includes any anti-IL-15 antibody for being described herein or illustrating and is being used to treat rheumatoid arthritis Method in use the antibody specification.In some respects, medicine box includes any anti-IL-15 antibody for being described herein or illustrating With the specification for using the antibody in the method for treating psoriasis.In some respects, medicine box includes and is described herein or example Any anti-IL-15 antibody for showing and the specification that the antibody is used in the method for treating inflammatory bowel disease.In some respects, Medicine box is included any anti-IL-15 antibody for being described herein or illustrating and is resisted in the method for treating type 1 diabetes using this The specification of body.In some respects, medicine box includes any anti-IL-15 antibody for being described herein or illustrating and is being used to treat alopecia areata The specification of the antibody is used in the method for disease.In some respects, medicine box includes that any anti-IL-15 for being described herein or illustrating resists Body and the specification that the antibody is used in the method for treating T cell large granular lymphocyte leukaemia.
Additionally provide the method for detecting the IL-15 from the tissue sample that subject separates.In general, such method packet Any anti-IL-15 antibody that including makes to be described herein or illustrate is contacted with the tissue sample separated from subject to form antibody-IL- 15 with IL-15 receptor alpha compound, and detection tissue sample in compound.The method may also include to be separated from subject Tissue sample.Tissue sample can come from gastrointestinal tissue, including esophageal tissue, gastric tissue, small intestine, Colorectal Tissues and come from Its hetero-organization of gastrointestinal tract.Antibody can be conjugated with detectable label.It can use the secondary antibody detection marked with detectable label Antibody.Such method can carry out in vivo, progress or original position carry out in vitro.
Additionally provide the compound for detecting IL-15 and IL-15 receptor alpha from the tissue sample that subject separates Method.In general, such method includes the tissue sample for separating any anti-IL-15 antibody for being described herein or illustrating with from subject Product contact is to form the Antibody-antigen complex for combining IL-15 with the anti-IL-15 antibody of IL-15 receptor alpha compound, Yi Jijian Survey the Antibody-antigen complex in tissue sample.The method may also include from subject's chorista sample.Tissue sample can To come from gastrointestinal tissue, including esophageal tissue, gastric tissue, small intestine, Colorectal Tissues and its hetero-organization from gastrointestinal tract.It is anti- Body can be conjugated with detectable label.It can use and detect antibody with the secondary antibody that detectable label marks.Such method can be It carries out in vivo, progress or progress in situ in vitro.
Following embodiment is provided so that the disclosure is more fully described.These embodiments are intended to the illustrative and not limiting disclosure. In embodiment, unless otherwise specified, referring to that the position of residue refers to the position in correlated series shown in this article.
Embodiment 1
Transgenic rat generates, immune and hybridoma generates
1.1 IL-15 albumen and IL-15R α albumen
Human interleukin 15 (IL-15) purchase obtains (Sigma), or uses the encoding human IL-15 of 1: 1 ratio and have The plasmid of the soluble IL-15 receptor alpha (IL-15R α) (SEQ ID NO:512) of the HIS and AVI label of N-terminal positioning is in lactation It is generated in animal HEK293F expression system.
1.2 transgenic rats generate
Transgenic rat is generated as described in PCT Publication No.WO 08/151081.In brief, by meganuclease Expression construct is integrated into the genome of animal subject.The expression of meganuclease leads to endogenous rat in reproduction cell The double-strand break of immunoglobulin gene.Such transgenic rat mating, which generates, has mutation/inactivation endogenous rat immune The offspring of globulin gene.
Transgenic rat is further modified so that it carries artificial immunoglobulin gene, so that rat energy It is enough to generate the antibody with complete people variable region.
1.3 immune
In order to generate the complete human monoclonal antibodies for combining IL-15 and IL-15 receptor alpha compound, with encoding human IL-15's The DNA immunization transgenic rat (generating as described above) of DNA and encoding human IL-15R α.
10 animals are immunized, and are answered in immunologic process with the plasma sample monitoring obtained by lower jaw bleed bottom is immune It answers.The antibody expression of blood plasma is screened by ELISA, and selects the animal of the anti-IL-15 antibody with enough titres for merging It is generated with hybridoma.Subcutaneously reinforce the animal with high titre with recombined human IL-15 compound, is put to death after 5 days.
1.4 generate the generation of the hybridoma of the monoclonal antibody in conjunction with IL-15 compound
In order to generate the hybridoma for generating the monoclonal antibody for combining IL-15 and IL-15 receptor alpha compound, moved from immune Object separating Morr. cell and lymph node cells simultaneously merge these cells with immortalized cell system.By the unicellular of lymphocyte Suspension and P3X63Ag8.653 non-secreting mouse myeloma cell (ATCC, CRL-1580) merge.By cell with about 1x105A cell/mL is spread in flat-bottom microtiter plates, then in addition to conventional reagent contain 10% tire polyclonal serum and It is incubated for 2 weeks in the selective medium of 1xHAT (Sigma).Then by ELISA andEach hole is screened to obtain There must be the human IL-15 IgG antibody of high-affinity.
Embodiment 2
Hybridoma screening
2.1 combine IL-15 compound using ELISA selection but do not combine the antibody of not compound IL-15 receptor alpha
With the IL-15 of the purifying or IL-15R α of purifying or the IL-15 composite coated microtiter plate of purifying.In short It, purifying protein of the microtiter plate in PBS is coated, and it is pure to be then used in diluted unrelated protein such as ox blood in PBS Albumen (BSA) closing.Doma supernatant dilution is added in each hole, and is incubated for 1-2 hours at 37 DEG C.Plate is used20 washing, then at 37 DEG C be conjugated to suitable detection reagent (such as horseradish peroxidase) The Goat anti-Human IgG Fc specific polyclonal reagent of alkaline phosphatase is incubated with 1 hour.After washing, with suitable substrate (such as 3,3 ', 5,5 '-tetramethyl benzidine TMD) make plate develop the color and are analyzed at 405 OD.Selection generates and IL-15 Compound has positive reaction but does not have the hybridoma of the antibody of positive reaction for further characterizing with IL-15R α.
2.2 combine IL-15 compound using ELISA (cELISA) selection based on cell but do not combine not compound IL- The antibody of 15 receptor alphas
By each hybridoma tested as described above in addition in the enzyme linked immunosorbent assay (ELISA) (cELISA) based on cell It is tested, to select to combine IL-15 compound but not combine the antibody of not compound IL-15R α.
It is following to carry out cELISA.HEK cell is transfected with the DNA of coding IL-15 and IL-15R α, so that these cells are expressed IL-15 compound.The HEK cell of transfection is coated on elisa plate, and the dilution of doma supernatant is coated on plate, Allow to be incorporated in the IL-15 compound expressed on cell surface.Using the HEK cell replication transfected with IL-15R α, So that these cells express not compound IL-15R α.It the use of the advantages of cELISA is also using natural egg in addition to classic ELISA White compound screening antibodies.
As positive control, anti-human IL-15- phycoerythrin (PE) antibody (R&D Systems, catalog number (Cat.No.) are used IC2471P IL-15 compound or the cell surface expression of not compound IL-15R α) are analyzed.Selection generates and IL-15 compound There is no the hybridoma of the antibody of positive reaction for further characterizing with positive reaction but with IL-15R α.
As a result representative selection is shown in FIG. 1.Antibody 4 combines not compound IL-15 and IL-15 compound, but not In conjunction with not compound IL15R α.Antibody 1A6 does not combine not compound IL-15, IL-15 compound or IL-15R α, its non-selected use In further characterization.Antibody 1B3 combines not compound IL-15, IL-15 compound and IL-15R α.In conjunction with not compound IL-15R α is unfavorable, because it indicate that clone is not IL-15 specificity.
Embodiment 3
Determine candidate antibodies for further developing
3.1 measurements based on CTLL-2 cell
In the measurement based on mouse CTLL-2 cell test combine IL-15 compound but do not combine 1500 of IL-15 α it is miscellaneous Tumor sample is handed over, to determine which neutralizes the bioactivity of IL-15.CTLL-2 cell line is originated from cytotoxic T cell lymthoma (ATCC:TIB-214) and to IL-2 and IL-15 there is response.
Test the ability that doma supernatant (unpurified antibody) neutralizes the CTLL-2 cell Proliferation of IL-15 induction.
Before test, CTLL-2 cell is incubated for 4 hours in the complete medium without IL-2 or IL-15.It will CTLL-2 cell (5x104A/hole) it is incubated in 96 orifice plates with the IL-15 of 200pM and IL-15 receptor alpha compound to lure Guided cell proliferation.Doma supernatant is added in plate and is incubated for 48 hours.Then it is used according to the explanation of manufacturerThe inhibition of luminescent cell vitality test (Promega) evaluation cell Proliferation, andIt is read on 96 microplate luminometers (Promega).Data are not shown.
3.2 Measurement
Parallel with the above-mentioned measurement based on cell, the IL-15 compound for being also tested for 1500 hybridomas combines activity, and Measure their affinity.It is measured using surface plasmon resonance (SPR).In single concentration analysis object by making in measurement With4000 biosensors (GE Healthcare) carry out SPR screening.By CM5Series S (GE Healthcare it) is docked in machine.It is standardized using Bia normalization solution (GE Healthcare).In docking chip Upper progress fluid dynamics addressing simultaneously passes through internal quality control inspection.
It is using amine coupling kit (GE Healthcare) that anti-rat Fc fragment antibody (Bethyl A110-136A) is solid It is scheduled on the surface of CM5 sensor chip.Antibody is diluted to the concentration of 50 μ g/mL in the sodium acetate of pH 4.5 in order to solid It is fixed, and the position on flow cell 1-4 is fixed on using HBS-EP+ buffer (GE Healthcare) and 10 minutes coupling times On point 1,2,4,5.All interactions are measured at 25 DEG C.This makes the fixed level in each site on four flow cells exist Between 10,000-12,000 response units.Use 100mM phosphate buffer regenerative cell.
Hybridoma is combined and is evaluated, 50 μ L Rat hybridoma supernatants are added in the HBS-EP+ running buffer of 70 μ L In.Use following methods:
Starting-regeneration 3 times circulations, 10 seconds every time, 30 μ L/min
Sample operation:
Capture-injection -30 μ L/min- normal injections-of site 1- flow cell 1-4-130 seconds are in this step by 4 differences Sample is loaded on the respective site 1 of four flow cells
Capture-injection -30 μ L/min- normal injections-of site 5- flow cell 1-4-130 seconds are in this step by 4 differences Sample is loaded on the respective site 1 of four flow cells
Sample-all sites is injected for all flow cells -60 seconds, and 60 seconds -30 μ L/min- normal injections of dissociation rate-are by people IL-15 compound (20 μ g/mL；Batch 491p90A) it is injected on all flow cells and all sites.
Regeneration 1-20 seconds, 100mM phosphoric acid
Regeneration 2-15 seconds, 100mM phosphoric acid
Regeneration 3-10 seconds, 100mM phosphoric acid
Another regeneration cycle-is carried out between each 96 orifice plate to carry out according to starting circulation.
Analysis
Using BiaEvaluation software, analyzed using dynamics capture.Analyze the sensing figure of 5-4 and 1-2. This allows to subtract IL-15 complex signal from the site without antibody.Site 3 is not used in analysis.Then analysis is each Sensing figure, will not show the combination of antibody and compound sample reject, and ratify display and IL-15 and IL-15 receptor alpha it is compound The sample of the combination of object.It carries out curve fitting, obtains affinity measured value table.
The sequencing of 3.3 variable regions
The molecular identity of antibody variable region in selected non-clone hybridoma agglomerate is established by RT-polymerase chain reaction.
In brief, it is at -80 DEG C(Thermo) in after freezen protective, hybridoma will be contained 96 orifice plates of agglomerate thaw.By plate with 1000xg rotation 5 minutes so that cell is agglomerating and removeBuffer. According to the scheme of manufacturer, GENELUTE is usedTM96 hole total serum IgE purification kits (Sigma#RTN9602, RTN9604) are from miscellaneous It hands in tumor plate and separates RNA.It uses8000 spectrophotometers (Thermo) measure the dense of gained RNA sample Degree and quality.Using oligo (dT) primer and AccuScript reverse transcriptase (Agilent#600184) by RNA reverse transcription at cDNA.CDNA synthetic reaction is assembled according to the scheme of manufacturer, and carries out cDNA synthesis at 42 DEG C, continues 30 minutes.
According to the instruction of manufacturer, passed through using PfuUltraII (Agilent) or Q5 high-fidelity DNA polymerase (NEB) PCR amplification is originated from the human antibody variable region in the hybridoma of transgenic rodents.Using to rodent heavy constant region DNA The special primer pair amplifies heavy chain of the DNA sequence dna of sequence and people's heavy chain leader sequence.Using to people λ constant region DNA sequences and people λ The special primer pair of the DNA sequence dna of chain leader sequence similarly expands lambda light chain variable area.
The PCR reaction of small equal portions is run on gel by using e- gel electrophoresis system (Thermo) to confirm variable region Successful amplification.According to the scheme of manufacturer, GENELUTE is usedTM96 hole PCR purification systems (Sigma#PCR9604) carry out Purification is reacted after PCR.The concentration of gained purifying DNA is evaluated using Nanodrop spectrophotometer.Using designed for internal junction (Sanger sequencing) is sequenced in the mulberry lattice for closing the oligonucleotides progress PCR fragment of heavy chain or light chain amplicon.By gained DNA sequence dna conceptual translations, for further analyzing, are generated for full length antibody chain later at amino acid sequence.Selection has only The antibody variable region (having the variation of at least one amino acid in complete sequence) of special amino acid sequence is anti-for being converted into overall length people Body.
The generation of 3.4 plasmids generated for antibody
It usesTechnology by variable region sequences reverse translation at DNA sequence dna, then by gained DNA assembles de novo formation by synthetic oligonucleotide (GeneArt, Germany).By the heavy chain and light-chain variable sequence of synthesis It is subcloned into containing human IgG1's heavy chain constant region (such as Swissprot accession number PO1857) or people's λ constant region (Swissprot Accession number P0CG05) mammalian expression vector in, to generate full length antibody chain.
The expression of 3.5 antibody
By the way that the plasmid co-transfection of encoding antibody heavy and light chain is arrivedCell (Life Technologies antibody is generated in).Cell number needed for the day before transfection, measurement experiment.Each 20mL is transfected, 20mL's3.6 × 10 are needed in expression culture medium7A cell.In the day before transfection, by cell with 0.9 × 106It is a Living cells/mL density is inoculated into TPP 50mL bioreactor pipe, and on the rail mounted oscillator rotated with 200rpm At 37 DEG C, containing 8%CO2Humid air atmosphere in be incubated overnight.On the day of transfection, cell is measured using automatic cell counter Several and vigor.Using only the culture of the living cells with > 98%.Each 20mL is transfected, by by 10 μ g heavy chain DNA and 10 μ g light chain DNA existI, which subtracts, is diluted to total volume as 1.0mL in blood serum medium (catalog number (Cat.No.) 31985-062) To prepare Lipid-DNA Complexes.By 54 μ L's293 reagents existI culture medium In be diluted to total volume be 1.0mL.Two bottles are gently mixed and are incubated at room temperature 5 minutes.It, will be diluted after incubation DNA with it is dilutedThe mixing of 293 reagents, and will293 examinations Agent composition is incubated for 20 minutes again at room temperature, to be formed with allowing293 reagents are compound Object.After incubation, by 2mL's293 reagent complex are added to each TPP 50mL biology In reactor tube.2mL is added into negative control pipeI culture medium replaces293 reagent complex.By cell on the rail mounted oscillator rotated with 200rpm It is incubated in 37 DEG C of incubators in the humid air atmosphere containing 8%CO2.About 16-18 hours after transfection, into each pipe It is added 100 μ L's293 transfection reinforcing agents 1 and 1.0mL293 Transfect reinforcing agent 2.About 72 hours harvest antibody after transfection.
The purifying of 3.6 antibody
By transfectionThe culture of cell is centrifuged 20 minutes in 50mL falcon pipe with 3000xg, and Use 0.22 μm of filter (Corning) filtering supernatant.Pass through protein A chromatography using Gilson ASPEC GX274 robot Method purifies supernatant antibody-containing.In brief, it is pre-equilibrated with the 1X PBS of 3 times of column volumes and 1.2mL MABSELECT is housedThe SPE cylinder (Agilent, 12131014) of Protein A resin (GE Healthcare).18mL supernatant is run on column Then liquid is washed with 4ml1X PBS.Each column is eluted in advance with 0.9mL0.1M citric acid (pH2.9).With 2mL 0.1M citric acid The antibody that (pH 2.9) is purified by flash.Using PD-10 column (GE Healthcare) by antibody desalination extremely PBS (59.5mM KH2PO4, 7.3mM Na2HPO4.2H2O, 145.4mM NaCl (pH~5.8)) in.
3 points of dilutions of 3.7 CTLL-2 cells
The ability for the CTLL2 cell Proliferation that every kind of antibody purification inhibits IL-15 to mediate is tested under three kinds of different dilutions.
Before test, CTLL-2 cell is incubated for 4 hours in the complete medium without IL-2 or IL-15.It will be thin Born of the same parents (5x104A/hole) it is incubated in 96 orifice plates with the IL-15 of 200pM and IL-15 receptor alpha compound, concentration induction 50% maximum cell is proliferated (EC50).Antibody diluent is added in plate and is incubated for 48 hours.Use three kinds of anti-IL-15 antibody Dilution: 2000pM, 200pM and 20pM.Then it is used according to the explanation of manufacturerLuminescent cell The inhibition of vitality test (Promega) evaluation cell Proliferation, andIt is read on 96 microplate luminometers (Promega) It takes.Data are expressed as relative light units, and (quantity of living cells is metabolic activity based on quantifying for existing ATP in culture The index of cell).
It is selected using this rough dose response of the ability for the bioactivity for functionally neutralizing IL-15 about antibody Antibody is for further analysis.As a result representative selection is shown in fig. 2.Antibody 4 is efficient IL-15 active antagonist.
The full dose response of 3.8 CTLL-2 cells
Selected antibody is run in 10 versions of above-mentioned CTLL-2 raji cell assay Raji, it is therefore an objective to it is bent to generate full dose response Line.
As a result representative selection is shown in fig. 2b.Use IC50(cell Proliferation reduces anti-IL-15 antibody when half to value Concentration) the opposite of every kind of antibody of evaluation inhibit spectrum.In the antibody of test, most effective antibody is antibody 4 and antibody 10F.
The full dose response of 3.9 NK-92 cells
Further raji cell assay Raji is carried out to antibody most effective in CTLL-2 raji cell assay Raji using NK-92 cell.This is thin Born of the same parents system is originated from NK Chlorambucil (ATCC:CRL-2407).
Before test, NK-92 cell is incubated for 4 hours in the complete medium without IL-2 or IL-15.By cell (5x 104A/hole) in 96 orifice plates with 25pM (EC50) IL-15 and IL-15 receptor alpha compound be incubated with inducing cell Proliferation.Antibody dosage is added in plate and is incubated for 48 hours.Then it is used as described above according to the explanation of manufacturerThe inhibition of luminescent cell vitality test (Promega) evaluation cell Proliferation, andIt is read on 96 microplate luminometers (Promega).Data are expressed as relative light units.
As a result representative selection is shown in FIG. 3.The opposite of every kind of antibody, which is evaluated, using IC50 value inhibits spectrum.Antibody 4 With minimum inhibition IC50 value (0.1nM, and be confirmed as the most effective inhibition of the proliferation based on cell of IL-15 driving Agent.
Embodiment 4
The modification of antibody
Change antibody 4, it is therefore an objective to positive influence be generated to the biophysical properties of antibody, and improve effect.
4.1 for the position in conjunction with vital amino acid
Pass through each residue in modification CDR sequence and evaluates the influence (CDR scanning) to Antibody Efficacy and binding characteristic To generate the variant of parental antibody.By the way that residue is modified to alanine (A), aspartic acid (D), histidine (H), lysine (K), leucine (L), glutamine (Q), serine (S), tryptophan (W) or tyrosine (Y) generate 9 in each position CDR Variant.Selecting this 9 amino acid is because they have series of characteristics, so that all functional characteristics can be tested, such as institute in table 1 Show.
1. aminoacid functional characteristic of table.
This cause to select antibody 4~520 kinds of variants, every kind of variant differs 1 amino acid with antibody 4.It produces as previously described Raw antibody, and made in Biacore T200 (GE Healthcare) system using CM5 albumin A (GE Healthcare) chip It is screened with surface plasmon resonance.Running buffer used is HBS-EP+ (GE Healthcare), at 25 DEG C It measures all interactions and data collection rate is set as 10Hz.Before running this method, starting circulation is carried out, wherein With two flow cells of two continuous 60s 0.1M citric acid (pH 3.0) pulse cleaning chips.
Antibody variants will be co-expressedThe supernatant of F cell is with 1: 100 in HBS-EP+ (GE Healthcare dilution in), and human IL-15 compound is diluted to 10 μ g/mL in same buffer.By antibody capture to core On second flow cell of piece, and by injecting 30 μ L human IL-15 compounds simultaneously with the flow velocity of 30 μ L/min in two flow cells 120 seconds Dissociation times are stayed to measure combination.Two continuous 60s 0.1M citric acids (pH3.0) are used on two flow cells Pulse, between cycles regeneration chip surface.
It is analyzed using the data from FC2-1.Sensing figure obtained by being analyzed as two customized reporting points of creation, Each reporting point is that just (' combining in early days ') or dissociation terminate 1 second that first 5 seconds (' later period combination ') starts 5 seconds after injected sample What window was calculated.Ratio based on the two reporting points (' later period combination '/' combining in early days ') carries out ranking to antibody, uses Make the estimation to dissociation rate.Opposite capture level is used as to the rough index of productivity.The result of CDR modification experiment is in Fig. 5- It is shown in Figure 34.Fig. 5-Figure 33 is shown so that the improved single modification (gray shade) of antibody, and Figure 34 is summarized and surveyed Examination makes the improved single and multiple modifications of antibody.
These experiments determined to combine and the vital amino acid of effect and being substituted combine without causing or The amino acid that effect changes.Surprisingly it was found that by aromatic amino acid Y or W replace heavy chain CDR2 in the 54th or 56th amino acids increase Antibody Efficacy.
Other variant is generated to test aromatic amino acid phenylalanine (F) to the 54th in heavy chain CDR2 or the 56th ammonia The substitution of base acid.Both variants also show the increase of effect in NK-92 cell proliferating determining.
Double variants are generated, wherein the 54th of heavy chain CDR2 or the 56th amino acids are all modified to Y, W or F.Such as chapters and sections The effect of double variants is evaluated described in 3.9 in NK-92 cell proliferating determining.As a result it is shown in table 2.
The bis- variants of 2. 54-56 of table.
It was found that not resisting mutually at the 54th with the effect that the 56th includes two aromatic amino acids, make effect tired instead Product improves.
Compared with antibody 4, antibody 11 (including 54Y and 56Y) IC in NK-92 cell proliferating determining50At least improve 10 Again (Figure 35 and table 3).
4.2 modification antibody 4 are to reduce potential immunogenic epitopes
In order to remove potential immunogenic epitopes in antibody, peptide sequence can be replaced, it will be in the region Sequence reverts to germline antibody sequence.182aS in heavy chain replaces (antibody 63) to generate Germline sequences and eliminates the region The immunogenic peptide of middle prediction.This, which is substituted in NK-92 measurement, does not influence effect, (antibody 63 and antibody as shown in table 3 11 compare).
N30S in light chain replaces (antibody 73) to generate Germline sequences and eliminates the immunogenicity predicted in the region Peptide.This is substituted in NK-92 measurement and generates minimal effect, (antibody 73 is compared with antibody 11) as shown in table 3 to effect.
Be combined to a kind of antibody when replacing both, i.e., in antibody 64 when, observe that effect is slight compared with antibody 11 It reduces (Figure 35).
The list for the variant that 3. immunogenicity of table reduces
4.3 modification antibody 64 are to improve manufacturability
The amino acid analysis that variable heavy chain and sequence of light chain to antibody 64 and associated antibodies carry out has determined may experience The amino acid of isomerization.Over time, the variation of these amino acid may change the stability of antibody.In light chain In, it determines D92 and S93 is potential aspartic acid isomerization site.In order to reduce the potential impact of these forecasting problems, generate The variant of antibody 64, these variants contain conservative or semi-conservative amino acid substitution in these positions.These replace and its it is right The influence of the effect of gained variant is listed in table 4.Figure 35 shows the generation for the variant tested in NK-92 cell proliferating determining Table selection.
Cause effect forfeiture (referring to antibody 68 compared with antibody 11) will to enhance the modification of manufacturability by changing D92 S93, which changes into L93, unexpectedly improves Antibody Efficacy, as shown in table 3 and Figure 35.
It is given in table 4 in order to generate the summary for the modification that antibody 70 carries out antibody 4.
The modification of table 4. is summarized
Embodiment 5
The receptor affinity and selectivity of 70 variant of antibody
Generate the constant region variant of antibody 70.It with frame is synthesized with human IgG isotype constant domain described in table 5 anti- The heavy chain variable region of body 70.
5. antibody of table, 70 variant
70 variant of antibody SEQ ID NO
Antibody 70a 33
Antibody 70b 35
Antibody 70e 47
Antibody 70f 49
IL-15 and the compound knot merga pass that is made of IL-15R α, IL-2R β and IL-2R γ its issue signal.Evaluation Cell factor such as IL-2, IL-4, IL-7, IL-9 and IL- of antibody and IL-15R α and shared coreceptor IL-2R β/γ 21 abilities combined.70 variant of antibody is not in conjunction with IL-15R α, IL-2, IL-4, IL-7, IL-9 and IL-21.
Existed using albumin A sensor chip (GE Healthcare) T200(GE Healthcare) The combination of surface plasmon resonance evaluation 70 variant of antibody and human IL-15 and IL-15 receptor alpha compound is used in system.It will Antibody capture is 150-200RU up to level to the second flow cell.The cell factor of purifying is diluted to 10 μ in HBS-EP+ g/mL.By injecting each cell factor of 45 μ L in two flow cells with the flow velocity of 30 μ L/min and staying 180 seconds Dissociation times To measure combination.With two 50mM sodium hydroxide pulses in 10 seconds regeneration chip surface between cycles.Runtime buffer used Liquid is HBS-EP+ (GE Healthcare), and all interactions are measured at 25 DEG C and are set as data collection rate 10Hz。
The summary of surface plasmon resonance data is shown in FIG. 36.It can be by KD (between antibody and its antigen Equilibrium dissociation constant) measurement affinity.Compared with antibody 4 (average KD=0.629nM) and AMG714 (average KD=1.84nM), The KD value of 70 variant of antibody is minimum (from 0.133 to 0.193nM).Huge KD difference between 70 variant of antibody and AMG714 is derived from Dissociation rate (kd).Fast ten times of rate of speed ratio IL-15 and 70 variant of the antibody dissociation that IL-15 and AMG714 is dissociated.Once In conjunction with IL-15, antibody 70 and its variant are kept for the time combined longer therefore more superior in terms of inhibiting IL-15 activity.This It is tested in the efficacy determinations based on cell.
Increase in IL-15 and IL-15 the receptor alpha compound inducing cell using 25pM (EC50) as described in example 3 above The effect of antibody 70 variant and AMG714 has been evaluated in the NK-92 proliferation assay grown.Figure 37 and table 6 show 70 variant of antibody IC50IC than AMG71450Low 83 to 98 times.Therefore, resist in terms of inhibiting IL-15 activity in the efficacy determinations based on cell Body 70 is more superior.
The IC of anti-IL-15 antibody in table 6:NK-92 proliferation assay50Value
Then research antibody 70F, obtains the average affinity to epitope, KD 430pM.To sum up, these result tables Bright, compared with AMG714,70 variant of antibody has the improved binding ability, affinity and effect to human IL-15.
Embodiment 6
The epitope mapping of antibody 70
Epitope mapping is carried out using Alanine scanning experiment.It carries out modeling analysis and is not involved in IL-15R α on IL-15 to determine In conjunction with possible exposure residue.Then IL-15 construct is designed, it is every in the residue for wherein theoretically exposing these One is replaced with alanine.The list of these variants is listed in table 7
The list of table 7:IL-15 alanine variant
Then these constructs and IL-15R α are co-expressed, and the supernatant using SPR test from expression culture Protein expression and and antibody 70a combination.
Running buffer used is HBS-EP+ (GE Healthcare).All interactions are measured at 25 DEG C and are incited somebody to action Data collection rate is set as 10Hz.It is analyzed using the data from FC2-1.By creation two customized reporting points come Analysis gained sensing figure, each reporting point be just 10 seconds after injected sample (" combining in early days ") or dissociate terminate first 10 seconds (" after Phase combination ") 5 seconds windows starting are calculated.Never these values are subtracted in the value of transfection control, and estimate opposite dissociation speed Rate, mode are to take the ratio of the two customized reporting points (" later period combination "/" combining in early days ") first, then take resulting value with For the score for the value that wild type human IL-15 and IL-15 receptor alpha compound calculate (data are not shown).
In order to confirm showing as a result, wild type human IL-15 and IL-15 receptor alpha compound will be compared for supernatant screening Faster the Sample Purification on Single of dissociation rate and retested by SPR.It will using albumin A sensor chip (GE Healthcare) It is 150-200RU that antibody 70a, which captures the second flow cell up to capture level,.The IL-15 alanine of purifying is scanned into construct It is diluted to 10 μ g/mL in HBS-EP+, then carries out 2 times of dilution series.By in two flow cells with the stream of 30 μ L/min Each dilution of 45 μ L of speed injection simultaneously stays 600 seconds Dissociation times to measure combination.It is being followed with 50mM sodium hydroxide pulse in 10 seconds Regeneration chip surface between ring.Running buffer used is that HBS-EP+ (GE Healthcare) measures all phases at 25 DEG C Data collection rate is simultaneously set as 10Hz by interaction.It is analyzed using the data from Fc2-1, and uses 1: 1 Lang Gemiao The sensing figure (being fitted using part Rmax) that your equation model generates is to determine KD.With all IL-15 third of IL-15R α coexpression The data of propylhomoserin variant are shown in FIG. 38, and the combination level for the anti-IL-15 antibody that these variants show and test reduces.Antibody 70a and the mutation combination level of IL-15 that there is Q108A to replace are low.The AMG714 and mutation IL- with following amino acid substitution 15 do not combine or combine horizontal significantly reduce: E98A, Q101A, H105A and Q108A.These are the result shows that this 4 kinds of amino acid Mutation destroy the combination of AMG714 and IL-15 and IL-15 receptor alpha compound, and the mutation of only Q108 destroys antibody The combination of 70a and IL-15 and IL-15 receptor alpha compound.It is in Figure 38 the results show that for the residue in the IL-15 of test, The combination for changing AMG714 antibody after these residues reduces, and antibody 70a in conjunction with will not be reduced because of change because of the antibody There is high-affinity to IL-15；Only the change of Q108 causes the combination of antibody 70a to reduce in IL-15.
Level is not combined or combined with the Q108A mutant of IL-15 in view of both antibody (antibody 70a and AMG714) It is low, other screening is carried out to antibody 70a using another anti-IL-15 antibody for combining Q108 and wild type IL-15 compound, The identical proof Q108A mutant of affinity correctly folds.Alanine scanning, which has been determined, can destroy antibody and IL-15 when mutation In conjunction with residue.In order to determine the definite residue contacted with IL-15 and thereby determine that epitope in conjunction with antibody 70a, pass through X-ray crystalline substance The interaction of body characterization antibody 70a and human IL-15.
When preparing for crystallization experiment, from bacterial expression recombined human IL-15 and purify.It is mediated by papain Antibody hinge cracking (opening antibody FAb and Fc points) prepares antibody 70a Fab (wherein FAb is antigen-binding fragment).FAb is led to Cross standard protein A chromatography purifying and it is compound with IL-15.FAb:IL-15 is purified by size exclusion chromatography, and using dilute It dredges matrix crystallization screening and carries out crystallization screening.Final crystal for Diffraction Data Collection is at 10% polyethylene glycol (PEG) 20000,20%PEG 500 monomethyl ethers (MME), 30mM CaCl2, 30mMMgCl2, the unspecified imidazoles/Phytar of 100mM It is formed in sodium/MES (acid)/Bis-Tris buffer solution mixture (pH 6.5).In diamond synchrotron (Diamond Synchrotron it) is had collected at the light beam line i04 of facilityDiffraction data.The public affairs of user's IL-15 and FAb molecule Opening structure parses the structure as the template for establishing model, by molecular replacement.Structure is iterated carefully according to experimental data Change, obtaining R/Rfree value is 23.6/28.9.The structure shows IL-2R γ and IL- of the variable region in human IL-15 of antibody 70a It is combined at 2R β binding site, to block those receptor units and the interaction (Figure 39 A and Figure 39 B) of IL-15.Pass through sight The interaction for examining IL-15 side chain Yu FAb side chain, by the mutual of the interaction and IL-15 side chain and IL-2R γ and IL-2R β Effect is compared and finds side chain that both interact common or residue further demonstrates above-mentioned conclusion.
Table 8 lists the interaction between IL-15 side chain and the side chain of the FAb segment of antibody 70a.It is contacted with IL-15 Antibody 70a FAb side chain formed antibody 70a and associated antibodies paratope.The explanation provided in table corresponds to: " hydrophobic phase Van der Waals interaction between interaction "-atom pair；The hydrogen bond that water mediates between " water mediates "-atom pair；" hydrogen bond "- ?Between heteroatomic hydrogen bond；" H- π hydrogen bond "-corresponds to donor/acceptor atom hydrogen bond in aromatic ring
The side chain of the FAb of table 8-IL-15 and antibody 70a interacts
Similar analysis has been carried out to the x-ray structure of level Four IL-15 receptor complex (pdb code 4GS7).Table 9 is based on The hydrogen occurred between IL-15 side chain and IL-2R γ and IL-2R β side chain is bonded, and shows IL-15 residue for IL-15 compound And the importance of the combination of IL-2R γ and IL-2R β.
The side chain of table 9-IL-15 and IL-2R γ and IL-2R β interacts
It is with the Solvent accessible surface formed when human IL-15 interaction in antibody 70 The value is to make It is calculated in PYMOL with the method for Strake and Rupley (1973) J.Mol.Biol.79:351-71.
The side chain of side chain interaction and IL2R β and γ chain and IL-15 by antibody 70a FAb and IL-15 interacts It is compared, it is determined that several common residues.S7 (Ser7) and IL-2R β forms hydrogen bond, and Q108 (Gln108) and N112 (Asn112) hydrogen bond (Figure 39 C- Figure 39 E) is formed with IL-2R γ.This 3 residues also form epitope, antibody 70a on IL-15 FAb is in conjunction with the epitope and forms hydrogen bond, so that IL-15 and IL-2R β and IL-2R γ be prevented to interact.
It include triple tyrosine of Y52/54/56 in the CDRH2 found during the affinity and effect of antibody 70a are mature Motif is the key that antibody determinant in conjunction with human IL-15.It checks crystal structure (Figure 39 F- Figure 39 H), it can be seen that the motif The hydrophobic residue around IL-15 spiral 4 is covered and protected, solvation is prevented and makes stable structure.
Embodiment 7
Pass through the combination of Flow cytometry primary human cell upper variant and IL-15
In order to further characterize antibody, the ability that they combine IL-15 on primary human cell is tested.It uses Lymphoprep (Axis-Shield, Lymphoprep) is separated from buffy coat and is purified human peripheral mononuclear cell (PBMC), And the combination of leading Ab is evaluated by flow cytometry.
Every hole is inoculated with 1x 10 first in 96 hole polypropylene boards (Sigma/Coming)6A PBMC living, and used at 4 DEG C Zombie Violet dyestuff (Biolegend) dyes 20 minutes.Cell is used at room temperature diluted in FACS buffer solution TruStain FcX Fc confining liquid (Biolegend) further dyes 10 minutes.For padding, by PBMC with 10 μ g/mL Test or Isotype control antibodies (being shown in Table 10) dyeing, and be incubated for 20 minutes at 4 DEG C.After immunostaining, then according to The explanation of manufacturer BD cytofix/cytoperm (BD Biosciences) fixed sample, and store at 4 DEG C until dividing Analysis.For cell inner dyeing, before dyeing with BD cytofix/cytoperm (BD Biosciences) fixed PBMC.Make Sample is analyzed with BD FACSCanto II (BD Biosciences).
Initial dual identification is carried out to remove cell aggregation from analysis to all cell events.Using viability dye Living cells is selected after excluding dead cell.Initial strobe is carried out to leucocyte, cell is divided into following cell: CD3-CD8-Cell, CD3+CD8+T cell and CD3+CD8-(putatively CD4+) T cell.Further analysis CD3- group by cell be divided into CD19+B cell and CD19- cell colony.In addition latter kind of groups is gated again with select CD56dimCD16+ and CD56briCD16dim/-NK cell.In addition, based on the level that CD14 and CD16 is expressed, then by monocyte (Hi SSC groups Body) it is subdivided into three kinds of primary monocytes subgroups: classical (CD14+CD16-), intermediate (CD14intCD16int) He Feijing (CD14dimCD16+) of allusion quotation.
It usesV.10, analysis software carries out data analysis.
The list of table 10. antibody and conjugate.
Representative combine of 70 variant of antibody is shown in FIG. 40 on monocyte.It is (classical in all monocytic subpopulations , it is intermediate and non-classical) cell surface on detect the medium combination of 70 variant of antibody.In all monocytic subpopulations In, it is horizontal that higher combination is reported in combination in the cell.Discovery combines detection level between two kinds of 70 variants of antibody Nuance.In T CD4+And CD8+Combination is not detected on the surface of all subgroups of cell and NK cell or detects low knot Heshui is flat, and data are not shown.These results instruction 70 variant of antibody can combine human IL-15 on primary cell.
Embodiment 8
The effect of anti-IL-15 antibody in animal model
The internal neutralization of 8.1 human IL-15s and IL-15 and IL-15 receptor alpha compound
The research is carried out to determine that recombined human IL-15 or IL-15/IL-15R α compound induces NK in C57BL/6 mouse With the degree in the degree and exemplary antibodies of the invention of the amplification of NKT cell with this induction.
(before first time cytokine injections 1 hour) is given into the group peritonaeum of 8 male C57B1/6 mouse on day 1 Give the antibody 70f (10,3,1,0.3 or 0.1mg/kg) or isotype controls (10mg/kg) of single dose.It day is held from the 1st day to the 3rd Continuous 3 days daily intraperitoneal injection recombinations IL-15 compound (wherein IL-15R α is Fc chimera) (1.5 μ g/ mouse), thus lure Lead NK1.1+ cell.On day 4, the spleen of mouse is harvested.Cell suspending liquid is prepared from total spleen of every mouse, and automatic thin It is counted on born of the same parents' counter.Based on the % of total splenocyte, NK1.1+ number is evaluated from cell suspending liquid by flow cytometry.Use algae The anti-mouse NK-1.1 (BD553165) of Lactoferrin conjugation.50,000 event/samples are obtained on cell counter.
As shown in Figure 41, the NK1.1+ cells accumulation in IL-15/IL-15R α compound inducing mouse spleen is injected.Pass through It is treated with the antibody 70f of 0.3mg/kg rather than employment Isotype control antibodies are treated, this product can be significantly inhibited It is poly-.
Influence of the 8.2 anti-IL-15 antibody to the circulation NK cell number of non-human primate
It previously has proven to apply anti-IL-15 antibody and can reduce circulation NK cell number (Lebrec et al. (2013) of machin J.Immunol.191:5551-5558).In order to further characterize antibody 70, antagonism IL-15 is tested in vivo to circulation NK cell Active consequence.Inject the antibody 70f's or 10mg/kg of 1 or 10mg/kg into the group single dose intravenous of 4 male machins Antibody 70b.By the 2nd, 5,8,15,30,45,60,75,90,102,120 and 150 day thin via streaming with research before administration The expression of born of the same parents' art analysis whole blood sample measurement NK cell marker CD159a (NKG2A) recycles NK cell number to quantify.
Various time points and intermediate value (solid line) the peripheral blood NK cell counting of every monkey are shown in FIG. 42.Application 1 or The antibody 70b of the antibody 70f or 10mg/kg of 10mg/kg cause to significantly reduce from research the 7th day, thin lower than circulation NK before administration Born of the same parents' number, this reduction continues to research the 120th day in most animals.
Effect of the 8.3 anti-IL-15 antibody in non-human primate rhesus macaque chylous diarrhea model
The chronic diarrheal disease of a kind of entitled " gluten-sensitive enteropathy " is in stable breeding rhesus macaque of the feeding containing gluten feed It is described in subgroup.When feeding the diet containing seitan, seitan sensitivity rhesus macaque shows the S&S of chylous diarrhea, Including there are intestinal tissue transglutaminase autoantibodies, there are anti-gliadin serum antibody, absorption of nutrient ingredients reduce, Xenobiotic metabolism reduction, Villus atrophy, the reduction of intestinal flora diversity, chronic diarrhea, weight loss, cancer susceptibility and exempt from Epidemic disease heredity (MHC II is relevant) association (Bethune MT et al. (2008) PLoS ONE.3 (2): e1614).Gluten-free diet These clinical, histologies and Serological Characterization are changed, and being reintroduced back to seitan diet causes quickly to recur.It is interesting that coming Show that IL-15 is overexpressed (Sestak K et al. (2016) in jejunal tissue from the biopsy article of seitan sensitivity rhesus macaque Nutrients.8 (7): 401.)
Anti- IL-15 antibody of the invention is tested in the rhesus macaque with gluten-sensitive enteropathy inhibits seitan induction The ability of symptom.Such as Sestak et al., 2015；Described in 2016,6 seitan sensitivity rhesus macaquies of Xiang Suoyou apply gluten-free diet (GFD) and diet containing seitan (GD) to induce immune alleviation and relapsing stage respectively, it is characterised in that anti-gliadin (AGA) With anti-rotation glutaminase 2 (TG2) positive and negative plasma antibody response.After induction AGA/TG2 antibody recurrence, by antibody 70f is administered to animal weekly intravenous (i.v.) with the dosage of 10mg/kg (BW), and three animals continue 28 days (group 1), and three dynamic Object continues 90 days (group 2), while still feeding rhesus macaque diet containing seitan.Intestines biopsy article is taken in conceptual phase to measure villus height Degree is counted with Crypt depth ratio and intraepithelial lymphocyte (IEL).For transglutaminase -2 and resist from blood serum sample measurement The presence of the autoantibody of gliadin antibody.Researching and designing is shown in Figure 45 A.
According to the scheme Sestak et al. previously established, 2015；2016, assess AGA and TG2 blood plasma (IgG) antibody, GS intestines Disease, including morphometry assessment small intestinal villous height and Crypt depth, i.e. V/C ratio.Corresponding to immune recurrence (GD) and is alleviating (GFD) small intestinal biopsy activity object is collected at the beginning and end of time and anti-IL-15 Antybody therapy phase.Such as Sestak et al., 2016 It is described, it collects biopsy article and is handled to obtain intraepithelial lymphocyte (IEL) counting.
As a result:
The jejunum biopsy article collected from seitan sensitivity rhesus macaque is evaluated before and after, during anti-IL15 Antybody therapy, After morphometry assessment small intestine construction is height of naps and Crypt depth (V/C) ratio, display enteropathy is improved.It is eating When with seitan diet, the rhesus macaque in two groups all has significant height of naps, Crypt depth organization construction loss (Figure 45 B). Anti- IL15 Antybody therapy makes V/C ratio significantly improve (p < 0.0001), so that two groups of chylous diarrhea rhesus macaquies is all benefited, because all control Treat the small intestinal villous height of animal, i.e. V/C ratio all increase, degree reach with it is healthy be of the similar age compare quite (Figure 45 B).
In order to assess the effect of anti-IL-15 Antybody therapy in seitan sensitivity rhesus macaque, represent GD diet (6 months), The time point of GFD (3 months) and anti-IL-15 Antybody therapy (the 35th day and the 61st day) acquires biopsy samples, and compares these samples Small intestine IEL between product counts (Figure 45 C).Compared with the IEL taken in earlier time point when animal takes GD is counted, two The IEL of anti-IL15 Antybody therapy group, which is counted, significantly reduces (p < 0.0001).Although diet containing seitan is fed, in the 1st group of Henghe The anti-IL15 Antybody therapy of measurement in the 35th day (TD35) and the 2nd group of rhesus macaque TD61 makes IEL reduce degree and is greater than 3 after monkey treatment GFD bring reduces degree (p < 0.0001) (Figure 45 C) within a month.
Before treatment, there is the horizontal increasing when being exposed to seitan of the anti-gliadin antibody of 5 animals in 6 animals Add, and reduce (animal 1B is without AGA response) after edible gluten-free diet, this shows that these animals are sensitive to seitan (Figure 45 D). Anti- IL-15 is treated so that the AGA antibody of 5/5 animal with highly resistance gliadin (AGA) level is reduced before the treatment, this is It is surprising, because these animals are still exposed to GD.
In summary, as measured in rhesus macaque chylous diarrhea model, anti-IL15 Antybody therapy mitigates seitan induction Intestinal mucosa injury (improves V/C ratio), mitigates the mucous membrane of small intestine inflammation (reducing IEL to count) of seitan induction and reduces seitan induction Serum antibody (reduce anti-gliadin antibody).
The present disclosure is not limited to the embodiments of above description and illustration, but can within the scope of the appended claims into Row changes and modification.
Sequence table
<110>Cephalon, INC.
<120>antibody and application thereof of human IL-15 is specifically combined
<130> 2873.273PC01
<150> 62/437,143
<151> 2016-12-21
<160> 520
<170>PatentIn 3.5 editions
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<221>variant
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<223>X is N, Y, W or F
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<222> (84)..(84)
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Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gly
1 5 10 15
Thr Leu Ser Leu Thr Cys Ala Val Ser Gly Gly Ser Ile Ser Ser Ser
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Ile Gly Glu Ile Tyr His Xaa Gly Xaa Thr Asn Tyr Asn Pro Ser Leu
50 55 60
Lys Ser Arg Val Thr Ile Ser Val Asp Lys Ser Lys Asn Gln Phe Ser
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Leu Lys Leu Xaa Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys
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Ala Arg Glu Gly Ile Gly Trp Pro Ser Phe Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
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<212> PRT
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Ser Ser Glu Leu Thr Gln Asp Pro Ala Ala Ser Val Ala Leu Gly Gln
1 5 10 15
Thr Val Arg Ile Thr Cys Gln Gly Asp Thr Leu Arg Xaa Tyr Tyr Ala
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Gly Lys Asn Asn Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser Gly Ser
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Ser Ser Gly Asn Thr Ala Ser Leu Thr Ile Thr Gly Ala Gln Ala Glu
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Asp Glu Ala Asp Tyr Tyr Cys Asn Ser Arg Asp Xaa Ser Gly Lys Asn
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Ser Ser Glu Leu Thr Gln Asp Pro Ala Ala Ser Val Ala Leu Gly Gln
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Thr Val Arg Ile Thr Cys Gln Gly Asp Thr Leu Arg Xaa Tyr Tyr Ala
20 25 30
Ser Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Ile Leu Val Ile Tyr
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Gly Lys Asn Asn Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser Gly Ser
50 55 60
Ser Ser Gly Asn Thr Ala Ser Leu Thr Ile Thr Gly Ala Gln Ala Glu
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Asp Glu Ala Asp Tyr Tyr Cys Asn Ser Arg Asp Xaa Ser Gly Lys Asn
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Leu Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gln Pro Lys
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Ala Ala Pro Ser Val Thr Leu Phe Pro Pro Ser Ser Glu Glu Leu Gln
115 120 125
Ala Asn Lys Ala Thr Leu Val Cys Leu Ile Ser Asp Phe Tyr Pro Gly
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Ala Val Thr Val Ala Trp Lys Ala Asp Ser Ser Pro Val Lys Ala Gly
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Val Glu Thr Thr Thr Pro Ser Lys Gln Ser Asn Asn Lys Tyr Ala Ala
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Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys Ser His Arg Ser
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Tyr Ser Cys Gln Val Thr His Glu Gly Ser Thr Val Glu Lys Thr Val
195 200 205
Ala Pro Thr Glu Cys Ser
210
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Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gly
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Thr Leu Ser Leu Thr Cys Ala Val Ser Gly Gly Ser Ile Ser Ser Ser
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Asn Trp Trp Ser Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp
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Ile Gly Glu Ile Tyr His Tyr Gly Tyr Thr Asn Tyr Asn Pro Ser Leu
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Lys Ser Arg Val Thr Ile Ser Val Asp Lys Ser Lys Asn Gln Phe Ser
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Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys
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Ala Arg Glu Gly Ile Gly Trp Pro Ser Phe Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
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<213>homo sapiens (Homo sapiens)
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Ser Ser Glu Leu Thr Gln Asp Pro Ala Ala Ser Val Ala Leu Gly Gln
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Thr Val Arg Ile Thr Cys Gln Gly Asp Thr Leu Arg Ser Tyr Tyr Ala
20 25 30
Ser Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Ile Leu Val Ile Tyr
35 40 45
Gly Lys Asn Asn Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser Gly Ser
50 55 60
Ser Ser Gly Asn Thr Ala Ser Leu Thr Ile Thr Gly Ala Gln Ala Glu
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Asp Glu Ala Asp Tyr Tyr Cys Asn Ser Arg Asp Leu Ser Gly Lys Asn
85 90 95
Leu Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
100 105
<210> 6
<211> 214
<212> PRT
<213>homo sapiens (Homo sapiens)
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Ser Ser Glu Leu Thr Gln Asp Pro Ala Ala Ser Val Ala Leu Gly Gln
1 5 10 15
Thr Val Arg Ile Thr Cys Gln Gly Asp Thr Leu Arg Ser Tyr Tyr Ala
20 25 30
Ser Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Ile Leu Val Ile Tyr
35 40 45
Gly Lys Asn Asn Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser Gly Ser
50 55 60
Ser Ser Gly Asn Thr Ala Ser Leu Thr Ile Thr Gly Ala Gln Ala Glu
65 70 75 80
Asp Glu Ala Asp Tyr Tyr Cys Asn Ser Arg Asp Leu Ser Gly Lys Asn
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Leu Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gln Pro Lys
100 105 110
Ala Ala Pro Ser Val Thr Leu Phe Pro Pro Ser Ser Glu Glu Leu Gln
115 120 125
Ala Asn Lys Ala Thr Leu Val Cys Leu Ile Ser Asp Phe Tyr Pro Gly
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Ala Val Thr Val Ala Trp Lys Ala Asp Ser Ser Pro Val Lys Ala Gly
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Val Glu Thr Thr Thr Pro Ser Lys Gln Ser Asn Asn Lys Tyr Ala Ala
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Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys Ser His Arg Ser
180 185 190
Tyr Ser Cys Gln Val Thr His Glu Gly Ser Thr Val Glu Lys Thr Val
195 200 205
Ala Pro Thr Glu Cys Ser
210
<210> 7
<211> 119
<212> PRT
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Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gly
1 5 10 15
Thr Leu Ser Leu Thr Cys Ala Val Ser Gly Gly Ser Ile Ser Ser Ser
20 25 30
Asn Trp Trp Ser Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp
35 40 45
Ile Gly Glu Ile Tyr His Ser Gly Asn Thr Asn Tyr Asn Pro Ser Leu
50 55 60
Lys Ser Arg Val Thr Ile Ser Val Asp Lys Ser Lys Asn Gln Phe Ser
65 70 75 80
Leu Lys Leu Ile Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Glu Gly Ile Gly Trp Pro Ser Phe Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 8
<211> 108
<212> PRT
<213>homo sapiens (Homo sapiens)
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Ser Ser Glu Leu Thr Gln Asp Pro Ala Ala Ser Val Ala Leu Gly Gln
1 5 10 15
Thr Val Arg Ile Thr Cys Gln Gly Asp Thr Leu Arg Asn Tyr Tyr Ala
20 25 30
Ser Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Ile Leu Val Ile Tyr
35 40 45
Gly Lys Asn Asn Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser Gly Ser
50 55 60
Ser Ser Gly Asn Thr Ala Ser Leu Thr Ile Thr Gly Ala Gln Ala Glu
65 70 75 80
Asp Glu Ala Asp Tyr Tyr Cys Asn Ser Arg Asp Ser Ser Gly Lys Asn
85 90 95
Leu Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
100 105
<210> 9
<211> 214
<212> PRT
<213>homo sapiens (Homo sapiens)
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Ser Ser Glu Leu Thr Gln Asp Pro Ala Ala Ser Val Ala Leu Gly Gln
1 5 10 15
Thr Val Arg Ile Thr Cys Gln Gly Asp Thr Leu Arg Asn Tyr Tyr Ala
20 25 30
Ser Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Ile Leu Val Ile Tyr
35 40 45
Gly Lys Asn Asn Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser Gly Ser
50 55 60
Ser Ser Gly Asn Thr Ala Ser Leu Thr Ile Thr Gly Ala Gln Ala Glu
65 70 75 80
Asp Glu Ala Asp Tyr Tyr Cys Asn Ser Arg Asp Ser Ser Gly Lys Asn
85 90 95
Leu Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gln Pro Lys
100 105 110
Ala Ala Pro Ser Val Thr Leu Phe Pro Pro Ser Ser Glu Glu Leu Gln
115 120 125
Ala Asn Lys Ala Thr Leu Val Cys Leu Ile Ser Asp Phe Tyr Pro Gly
130 135 140
Ala Val Thr Val Ala Trp Lys Ala Asp Ser Ser Pro Val Lys Ala Gly
145 150 155 160
Val Glu Thr Thr Thr Pro Ser Lys Gln Ser Asn Asn Lys Tyr Ala Ala
165 170 175
Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys Ser His Arg Ser
180 185 190
Tyr Ser Cys Gln Val Thr His Glu Gly Ser Thr Val Glu Lys Thr Val
195 200 205
Ala Pro Thr Glu Cys Ser
210
<210> 10
<211> 30
<212> PRT
<213>homo sapiens (Homo sapiens)
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Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gly
1 5 10 15
Thr Leu Ser Leu Thr Cys Ala Val Ser Gly Gly Ser Ile Ser
20 25 30
<210> 11
<211> 14
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 11
Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile Gly
1 5 10
<210> 12
<211> 32
<212> PRT
<213>homo sapiens (Homo sapiens)
<220>
<221>variant
<222> (18)..(18)
<223>X is I or S
<400> 12
Arg Val Thr Ile Ser Val Asp Lys Ser Lys Asn Gln Phe Ser Leu Lys
1 5 10 15
Leu Xaa Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala Arg
20 25 30
<210> 13
<211> 32
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 13
Arg Val Thr Ile Ser Val Asp Lys Ser Lys Asn Gln Phe Ser Leu Lys
1 5 10 15
Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala Arg
20 25 30
<210> 14
<211> 32
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 14
Arg Val Thr Ile Ser Val Asp Lys Ser Lys Asn Gln Phe Ser Leu Lys
1 5 10 15
Leu Ile Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala Arg
20 25 30
<210> 15
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 15
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
1 5 10
<210> 16
<211> 6
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 16
Ser Ser Asn Trp Trp Ser
1 5
<210> 17
<211> 16
<212> PRT
<213>homo sapiens (Homo sapiens)
<220>
<221>variant
<222> (5)..(5)
<223>X is S, Y, W or F
<220>
<221>variant
<222> (7)..(7)
<223>X is N, Y, W or F
<400> 17
Glu Ile Tyr His Xaa Gly Xaa Thr Asn Tyr Asn Pro Ser Leu Lys Ser
1 5 10 15
<210> 18
<211> 16
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 18
Glu Ile Tyr His Tyr Gly Tyr Thr Asn Tyr Asn Pro Ser Leu Lys Ser
1 5 10 15
<210> 19
<211> 16
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 19
Glu Ile Tyr His Ser Gly Asn Thr Asn Tyr Asn Pro Ser Leu Lys Ser
1 5 10 15
<210> 20
<211> 10
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 20
Glu Gly Ile Gly Trp Pro Ser Phe Asp Tyr
1 5 10
<210> 21
<211> 22
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 21
Ser Ser Glu Leu Thr Gln Asp Pro Ala Ala Ser Val Ala Leu Gly Gln
1 5 10 15
Thr Val Arg Ile Thr Cys
20
<210> 22
<211> 15
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 22
Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Ile Leu Val Ile Tyr
1 5 10 15
<210> 23
<211> 32
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 23
Gly Ile Pro Asp Arg Phe Ser Gly Ser Ser Ser Gly Asn Thr Ala Ser
1 5 10 15
Leu Thr Ile Thr Gly Ala Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys
20 25 30
<210> 24
<211> 10
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 24
Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
1 5 10
<210> 25
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<220>
<221>variant
<222> (7)..(7)
<223>X is N or S
<400> 25
Gln Gly Asp Thr Leu Arg Xaa Tyr Tyr Ala Ser
1 5 10
<210> 26
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 26
Gln Gly Asp Thr Leu Arg Ser Tyr Tyr Ala Ser
1 5 10
<210> 27
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 27
Gln Gly Asp Thr Leu Arg Asn Tyr Tyr Ala Ser
1 5 10
<210> 28
<211> 7
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 28
Gly Lys Asn Asn Arg Pro Ser
1 5
<210> 29
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<220>
<221>variant
<222> (5)..(5)
<223>X is S, L or F
<400> 29
Asn Ser Arg Asp Xaa Ser Gly Lys Asn Leu Val
1 5 10
<210> 30
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 30
Asn Ser Arg Asp Leu Ser Gly Lys Asn Leu Val
1 5 10
<210> 31
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 31
Asn Ser Arg Asp Ser Ser Gly Lys Asn Leu Val
1 5 10
<210> 32
<211> 330
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 32
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys
1 5 10 15
Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr
65 70 75 80
Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys
100 105 110
Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro
115 120 125
Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
130 135 140
Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
145 150 155 160
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
165 170 175
Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
180 185 190
His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
195 200 205
Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
210 215 220
Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu
225 230 235 240
Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
245 250 255
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
260 265 270
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
275 280 285
Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
290 295 300
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
305 310 315 320
Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
325 330
<210> 33
<211> 329
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 33
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys
1 5 10 15
Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr
65 70 75 80
Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys
100 105 110
Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro
115 120 125
Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
130 135 140
Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
145 150 155 160
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
165 170 175
Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
180 185 190
His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
195 200 205
Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
210 215 220
Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu
225 230 235 240
Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
245 250 255
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
260 265 270
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
275 280 285
Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
290 295 300
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
305 310 315 320
Gln Lys Ser Leu Ser Leu Ser Pro Gly
325
<210> 34
<211> 330
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 34
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys
1 5 10 15
Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr
65 70 75 80
Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys
100 105 110
Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro
115 120 125
Lys Pro Lys Asp Thr Leu Tyr Ile Thr Arg Glu Pro Glu Val Thr Cys
130 135 140
Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
145 150 155 160
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
165 170 175
Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
180 185 190
His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
195 200 205
Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
210 215 220
Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu
225 230 235 240
Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
245 250 255
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
260 265 270
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
275 280 285
Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
290 295 300
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
305 310 315 320
Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
325 330
<210> 35
<211> 329
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 35
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys
1 5 10 15
Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr
65 70 75 80
Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys
100 105 110
Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro
115 120 125
Lys Pro Lys Asp Thr Leu Tyr Ile Thr Arg Glu Pro Glu Val Thr Cys
130 135 140
Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
145 150 155 160
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
165 170 175
Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
180 185 190
His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
195 200 205
Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
210 215 220
Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu
225 230 235 240
Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
245 250 255
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
260 265 270
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
275 280 285
Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
290 295 300
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
305 310 315 320
Gln Lys Ser Leu Ser Leu Ser Pro Gly
325
<210> 36
<211> 330
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 36
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys
1 5 10 15
Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr
65 70 75 80
Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys
100 105 110
Pro Ala Pro Glu Leu Ala Gly Ala Pro Ser Val Phe Leu Phe Pro Pro
115 120 125
Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
130 135 140
Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
145 150 155 160
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
165 170 175
Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
180 185 190
His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
195 200 205
Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
210 215 220
Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu
225 230 235 240
Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
245 250 255
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
260 265 270
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
275 280 285
Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
290 295 300
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
305 310 315 320
Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
325 330
<210> 37
<211> 329
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 37
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys
1 5 10 15
Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr
65 70 75 80
Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys
100 105 110
Pro Ala Pro Glu Leu Ala Gly Ala Pro Ser Val Phe Leu Phe Pro Pro
115 120 125
Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
130 135 140
Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
145 150 155 160
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
165 170 175
Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
180 185 190
His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
195 200 205
Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
210 215 220
Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu
225 230 235 240
Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
245 250 255
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
260 265 270
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
275 280 285
Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
290 295 300
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
305 310 315 320
Gln Lys Ser Leu Ser Leu Ser Pro Gly
325
<210> 38
<211> 330
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 38
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys
1 5 10 15
Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr
65 70 75 80
Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys
100 105 110
Pro Ala Pro Glu Ala Ala Gly Ala Pro Ser Val Phe Leu Phe Pro Pro
115 120 125
Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
130 135 140
Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
145 150 155 160
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
165 170 175
Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
180 185 190
His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
195 200 205
Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
210 215 220
Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu
225 230 235 240
Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
245 250 255
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
260 265 270
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
275 280 285
Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
290 295 300
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
305 310 315 320
Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
325 330
<210> 39
<211> 329
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 39
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys
1 5 10 15
Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr
65 70 75 80
Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys
100 105 110
Pro Ala Pro Glu Ala Ala Gly Ala Pro Ser Val Phe Leu Phe Pro Pro
115 120 125
Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
130 135 140
Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
145 150 155 160
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
165 170 175
Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
180 185 190
His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
195 200 205
Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
210 215 220
Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu
225 230 235 240
Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
245 250 255
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
260 265 270
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
275 280 285
Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
290 295 300
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
305 310 315 320
Gln Lys Ser Leu Ser Leu Ser Pro Gly
325
<210> 40
<211> 326
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 40
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg
1 5 10 15
Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Asn Phe Gly Thr Gln Thr
65 70 75 80
Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Thr Val Glu Arg Lys Cys Cys Val Glu Cys Pro Pro Cys Pro Ala Pro
100 105 110
Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp
115 120 125
Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp
130 135 140
Val Ser His Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly
145 150 155 160
Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn
165 170 175
Ser Thr Phe Arg Val Val Ser Val Leu Thr Val Val His Gln Asp Trp
180 185 190
Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro
195 200 205
Ala Pro Ile Glu Lys Thr Ile Ser Lys Thr Lys Gly Gln Pro Arg Glu
210 215 220
Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn
225 230 235 240
Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile
245 250 255
Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr
260 265 270
Thr Pro Pro Met Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys
275 280 285
Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys
290 295 300
Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu
305 310 315 320
Ser Leu Ser Pro Gly Lys
325
<210> 41
<211> 325
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 41
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg
1 5 10 15
Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Asn Phe Gly Thr Gln Thr
65 70 75 80
Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Thr Val Glu Arg Lys Cys Cys Val Glu Cys Pro Pro Cys Pro Ala Pro
100 105 110
Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp
115 120 125
Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp
130 135 140
Val Ser His Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly
145 150 155 160
Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn
165 170 175
Ser Thr Phe Arg Val Val Ser Val Leu Thr Val Val His Gln Asp Trp
180 185 190
Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro
195 200 205
Ala Pro Ile Glu Lys Thr Ile Ser Lys Thr Lys Gly Gln Pro Arg Glu
210 215 220
Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn
225 230 235 240
Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile
245 250 255
Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr
260 265 270
Thr Pro Pro Met Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys
275 280 285
Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys
290 295 300
Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu
305 310 315 320
Ser Leu Ser Pro Gly
325
<210> 42
<211> 326
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 42
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg
1 5 10 15
Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Asn Phe Gly Thr Gln Thr
65 70 75 80
Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Thr Val Glu Arg Lys Cys Cys Val Glu Cys Pro Pro Cys Pro Ala Pro
100 105 110
Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp
115 120 125
Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp
130 135 140
Val Ser His Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly
145 150 155 160
Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn
165 170 175
Ser Thr Phe Arg Val Val Ser Val Leu Thr Val Val His Gln Asp Trp
180 185 190
Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro
195 200 205
Ser Ser Ile Glu Lys Thr Ile Ser Lys Thr Lys Gly Gln Pro Arg Glu
210 215 220
Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn
225 230 235 240
Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile
245 250 255
Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr
260 265 270
Thr Pro Pro Met Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys
275 280 285
Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys
290 295 300
Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu
305 310 315 320
Ser Leu Ser Pro Gly Lys
325
<210> 43
<211> 325
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 43
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg
1 5 10 15
Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Asn Phe Gly Thr Gln Thr
65 70 75 80
Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Thr Val Glu Arg Lys Cys Cys Val Glu Cys Pro Pro Cys Pro Ala Pro
100 105 110
Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp
115 120 125
Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp
130 135 140
Val Ser His Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly
145 150 155 160
Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn
165 170 175
Ser Thr Phe Arg Val Val Ser Val Leu Thr Val Val His Gln Asp Trp
180 185 190
Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro
195 200 205
Ser Ser Ile Glu Lys Thr Ile Ser Lys Thr Lys Gly Gln Pro Arg Glu
210 215 220
Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn
225 230 235 240
Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile
245 250 255
Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr
260 265 270
Thr Pro Pro Met Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys
275 280 285
Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys
290 295 300
Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu
305 310 315 320
Ser Leu Ser Pro Gly
325
<210> 44
<211> 327
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 44
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg
1 5 10 15
Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr
65 70 75 80
Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Ser Cys Pro Ala Pro
100 105 110
Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
115 120 125
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
130 135 140
Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp
145 150 155 160
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe
165 170 175
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
180 185 190
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu
195 200 205
Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
210 215 220
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys
225 230 235 240
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
245 250 255
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
260 265 270
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
275 280 285
Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser
290 295 300
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
305 310 315 320
Leu Ser Leu Ser Leu Gly Lys
325
<210> 45
<211> 326
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 45
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg
1 5 10 15
Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr
65 70 75 80
Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Ser Cys Pro Ala Pro
100 105 110
Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
115 120 125
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
130 135 140
Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp
145 150 155 160
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe
165 170 175
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
180 185 190
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu
195 200 205
Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
210 215 220
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys
225 230 235 240
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
245 250 255
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
260 265 270
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
275 280 285
Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser
290 295 300
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
305 310 315 320
Leu Ser Leu Ser Leu Gly
325
<210> 46
<211> 327
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 46
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg
1 5 10 15
Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr
65 70 75 80
Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro
100 105 110
Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
115 120 125
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
130 135 140
Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp
145 150 155 160
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe
165 170 175
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
180 185 190
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu
195 200 205
Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
210 215 220
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys
225 230 235 240
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
245 250 255
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
260 265 270
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
275 280 285
Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser
290 295 300
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
305 310 315 320
Leu Ser Leu Ser Leu Gly Lys
325
<210> 47
<211> 326
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 47
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg
1 5 10 15
Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr
65 70 75 80
Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro
100 105 110
Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
115 120 125
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
130 135 140
Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp
145 150 155 160
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe
165 170 175
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
180 185 190
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu
195 200 205
Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
210 215 220
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys
225 230 235 240
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
245 250 255
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
260 265 270
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
275 280 285
Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser
290 295 300
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
305 310 315 320
Leu Ser Leu Ser Leu Gly
325
<210> 48
<211> 327
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 48
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg
1 5 10 15
Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr
65 70 75 80
Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro
100 105 110
Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
115 120 125
Asp Thr Leu Tyr Ile Thr Arg Glu Pro Glu Val Thr Cys Val Val Val
130 135 140
Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp
145 150 155 160
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe
165 170 175
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
180 185 190
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu
195 200 205
Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
210 215 220
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys
225 230 235 240
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
245 250 255
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
260 265 270
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
275 280 285
Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser
290 295 300
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
305 310 315 320
Leu Ser Leu Ser Leu Gly Lys
325
<210> 49
<211> 326
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 49
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg
1 5 10 15
Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr
65 70 75 80
Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro
100 105 110
Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
115 120 125
Asp Thr Leu Tyr Ile Thr Arg Glu Pro Glu Val Thr Cys Val Val Val
130 135 140
Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp
145 150 155 160
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe
165 170 175
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
180 185 190
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu
195 200 205
Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
210 215 220
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys
225 230 235 240
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
245 250 255
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
260 265 270
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
275 280 285
Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser
290 295 300
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
305 310 315 320
Leu Ser Leu Ser Leu Gly
325
<210> 50
<211> 327
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 50
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg
1 5 10 15
Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr
65 70 75 80
Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Ser Cys Pro Ala Pro
100 105 110
Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
115 120 125
Asp Thr Leu Tyr Ile Thr Arg Glu Pro Glu Val Thr Cys Val Val Val
130 135 140
Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp
145 150 155 160
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe
165 170 175
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
180 185 190
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu
195 200 205
Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
210 215 220
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys
225 230 235 240
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
245 250 255
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
260 265 270
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
275 280 285
Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser
290 295 300
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
305 310 315 320
Leu Ser Leu Ser Leu Gly Lys
325
<210> 51
<211> 326
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 51
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg
1 5 10 15
Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr
65 70 75 80
Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Ser Cys Pro Ala Pro
100 105 110
Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
115 120 125
Asp Thr Leu Tyr Ile Thr Arg Glu Pro Glu Val Thr Cys Val Val Val
130 135 140
Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp
145 150 155 160
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe
165 170 175
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
180 185 190
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu
195 200 205
Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
210 215 220
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys
225 230 235 240
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
245 250 255
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
260 265 270
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
275 280 285
Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser
290 295 300
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
305 310 315 320
Leu Ser Leu Ser Leu Gly
325
<210> 52
<211> 6
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 52
Ala Ser Asn Trp Trp Ser
1 5
<210> 53
<211> 6
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 53
Ser Ala Asn Trp Trp Ser
1 5
<210> 54
<211> 6
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 54
Ser Ser Ala Trp Trp Ser
1 5
<210> 55
<211> 6
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 55
Ser Ser Asn Ala Trp Ser
1 5
<210> 56
<211> 6
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 56
Ser Ser Asn Trp Ala Ser
1 5
<210> 57
<211> 6
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 57
Ser Ser Asn Trp Trp Ala
1 5
<210> 58
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 58
Gly Ala Ser Ile Ser Ser Ser Asn Trp Trp Ser
1 5 10
<210> 59
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 59
Gly Gly Ala Ile Ser Ser Ser Asn Trp Trp Ser
1 5 10
<210> 60
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 60
Gly Gly Ser Ala Ser Ser Ser Asn Trp Trp Ser
1 5 10
<210> 61
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 61
Gly Gly Ser Ile Ala Ser Ser Asn Trp Trp Ser
1 5 10
<210> 62
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 62
Gly Gly Ser Ile Ser Ala Ser Asn Trp Trp Ser
1 5 10
<210> 63
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 63
Gly Gly Ser Ile Ser Ser Ala Asn Trp Trp Ser
1 5 10
<210> 64
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 64
Gly Gly Ser Ile Ser Ser Ser Ala Trp Trp Ser
1 5 10
<210> 65
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 65
Gly Gly Ser Ile Ser Ser Ser Asn Trp Trp Ala
1 5 10
<210> 66
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 66
Asp Gly Ser Ile Ser Ser Ser Asn Trp Trp Ser
1 5 10
<210> 67
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 67
Gly Asp Ser Ile Ser Ser Ser Asn Trp Trp Ser
1 5 10
<210> 68
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 68
Gly Gly Asp Ile Ser Ser Ser Asn Trp Trp Ser
1 5 10
<210> 69
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 69
Gly Gly Ser Asp Ser Ser Ser Asn Trp Trp Ser
1 5 10
<210> 70
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 70
Gly Gly Ser Ile Asp Ser Ser Asn Trp Trp Ser
1 5 10
<210> 71
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 71
Gly Gly Ser Ile Ser Asp Ser Asn Trp Trp Ser
1 5 10
<210> 72
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 72
Gly Gly Ser Ile Ser Ser Asp Asn Trp Trp Ser
1 5 10
<210> 73
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 73
Gly Gly Ser Ile Ser Ser Ser Asp Trp Trp Ser
1 5 10
<210> 74
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 74
Gly Gly Ser Ile Ser Ser Ser Asn Asp Trp Ser
1 5 10
<210> 75
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 75
Gly Gly Ser Ile Ser Ser Ser Asn Trp Trp Asp
1 5 10
<210> 76
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 76
His Gly Ser Ile Ser Ser Ser Asn Trp Trp Ser
1 5 10
<210> 77
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 77
Gly His Ser Ile Ser Ser Ser Asn Trp Trp Ser
1 5 10
<210> 78
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 78
Gly Gly His Ile Ser Ser Ser Asn Trp Trp Ser
1 5 10
<210> 79
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 79
Gly Gly Ser His Ser Ser Ser Asn Trp Trp Ser
1 5 10
<210> 80
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 80
Gly Gly Ser Ile His Ser Ser Asn Trp Trp Ser
1 5 10
<210> 81
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 81
Gly Gly Ser Ile Ser His Ser Asn Trp Trp Ser
1 5 10
<210> 82
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 82
Gly Gly Ser Ile Ser Ser His Asn Trp Trp Ser
1 5 10
<210> 83
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 83
Gly Gly Ser Ile Ser Ser Ser His Trp Trp Ser
1 5 10
<210> 84
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 84
Gly Gly Ser Ile Ser Ser Ser Asn His Trp Ser
1 5 10
<210> 85
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 85
Gly Gly Ser Ile Ser Ser Ser Asn Trp His Ser
1 5 10
<210> 86
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 86
Lys Gly Ser Ile Ser Ser Ser Asn Trp Trp Ser
1 5 10
<210> 87
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 87
Gly Lys Ser Ile Ser Ser Ser Asn Trp Trp Ser
1 5 10
<210> 88
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 88
Gly Gly Lys Ile Ser Ser Ser Asn Trp Trp Ser
1 5 10
<210> 89
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 89
Gly Gly Ser Lys Ser Ser Ser Asn Trp Trp Ser
1 5 10
<210> 90
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 90
Gly Gly Ser Ile Lys Ser Ser Asn Trp Trp Ser
1 5 10
<210> 91
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 91
Gly Gly Ser Ile Ser Lys Ser Asn Trp Trp Ser
1 5 10
<210> 92
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 92
Gly Gly Ser Ile Ser Ser Lys Asn Trp Trp Ser
1 5 10
<210> 93
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 93
Leu Gly Ser Ile Ser Ser Ser Asn Trp Trp Ser
1 5 10
<210> 94
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 94
Gly Leu Ser Ile Ser Ser Ser Asn Trp Trp Ser
1 5 10
<210> 95
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 95
Gly Gly Leu Ile Ser Ser Ser Asn Trp Trp Ser
1 5 10
<210> 96
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 96
Gly Gly Ser Leu Ser Ser Ser Asn Trp Trp Ser
1 5 10
<210> 97
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 97
Gly Gly Ser Ile Leu Ser Ser Asn Trp Trp Ser
1 5 10
<210> 98
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 98
Gly Gly Ser Ile Ser Leu Ser Asn Trp Trp Ser
1 5 10
<210> 99
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 99
Gly Gly Ser Ile Ser Ser Leu Asn Trp Trp Ser
1 5 10
<210> 100
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 100
Gly Gly Ser Ile Ser Ser Ser Leu Trp Trp Ser
1 5 10
<210> 101
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 101
Gly Gly Ser Ile Ser Ser Ser Asn Leu Trp Ser
1 5 10
<210> 102
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 102
Gly Gly Ser Ile Ser Ser Ser Asn Trp Leu Ser
1 5 10
<210> 103
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 103
Gly Gly Ser Ile Ser Ser Ser Asn Trp Trp Leu
1 5 10
<210> 104
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 104
Gln Gly Ser Ile Ser Ser Ser Asn Trp Trp Ser
1 5 10
<210> 105
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 105
Gly Gln Ser Ile Ser Ser Ser Asn Trp Trp Ser
1 5 10
<210> 106
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 106
Gly Gly Gln Ile Ser Ser Ser Asn Trp Trp Ser
1 5 10
<210> 107
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 107
Gly Gly Ser Gln Ser Ser Ser Asn Trp Trp Ser
1 5 10
<210> 108
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 108
Gly Gly Ser Ile Gln Ser Ser Asn Trp Trp Ser
1 5 10
<210> 109
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 109
Gly Gly Ser Ile Ser Gln Ser Asn Trp Trp Ser
1 5 10
<210> 110
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 110
Gly Gly Ser Ile Ser Ser Gln Asn Trp Trp Ser
1 5 10
<210> 111
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 111
Gly Gly Ser Ile Ser Ser Ser Gln Trp Trp Ser
1 5 10
<210> 112
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 112
Gly Gly Ser Ile Ser Ser Ser Asn Gln Trp Ser
1 5 10
<210> 113
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 113
Ser Gly Ser Ile Ser Ser Ser Asn Trp Trp Ser
1 5 10
<210> 114
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 114
Gly Ser Ser Ile Ser Ser Ser Asn Trp Trp Ser
1 5 10
<210> 115
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 115
Gly Gly Ser Ser Ser Ser Ser Asn Trp Trp Ser
1 5 10
<210> 116
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 116
Gly Gly Ser Ile Ser Ser Ser Ser Trp Trp Ser
1 5 10
<210> 117
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 117
Gly Gly Ser Ile Ser Ser Ser Asn Ser Trp Ser
1 5 10
<210> 118
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 118
Trp Gly Ser Ile Ser Ser Ser Asn Trp Trp Ser
1 5 10
<210> 119
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 119
Gly Trp Ser Ile Ser Ser Ser Asn Trp Trp Ser
1 5 10
<210> 120
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 120
Gly Gly Trp Ile Ser Ser Ser Asn Trp Trp Ser
1 5 10
<210> 121
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 121
Gly Gly Ser Trp Ser Ser Ser Asn Trp Trp Ser
1 5 10
<210> 122
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 122
Gly Gly Ser Ile Trp Ser Ser Asn Trp Trp Ser
1 5 10
<210> 123
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 123
Gly Gly Ser Ile Ser Trp Ser Asn Trp Trp Ser
1 5 10
<210> 124
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 124
Gly Gly Ser Ile Ser Ser Trp Asn Trp Trp Ser
1 5 10
<210> 125
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 125
Gly Gly Ser Ile Ser Ser Ser Trp Trp Trp Ser
1 5 10
<210> 126
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 126
Tyr Gly Ser Ile Ser Ser Ser Asn Trp Trp Ser
1 5 10
<210> 127
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 127
Gly Tyr Ser Ile Ser Ser Ser Asn Trp Trp Ser
1 5 10
<210> 128
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 128
Gly Gly Tyr Ile Ser Ser Ser Asn Trp Trp Ser
1 5 10
<210> 129
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 129
Gly Gly Ser Tyr Ser Ser Ser Asn Trp Trp Ser
1 5 10
<210> 130
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 130
Gly Gly Ser Ile Tyr Ser Ser Asn Trp Trp Ser
1 5 10
<210> 131
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 131
Gly Gly Ser Ile Ser Tyr Ser Asn Trp Trp Ser
1 5 10
<210> 132
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 132
Gly Gly Ser Ile Ser Ser Tyr Asn Trp Trp Ser
1 5 10
<210> 133
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 133
Gly Gly Ser Ile Ser Ser Ser Tyr Trp Trp Ser
1 5 10
<210> 134
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 134
Gly Gly Ser Ile Ser Ser Ser Asn Tyr Trp Ser
1 5 10
<210> 135
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 135
Gly Gly Ser Ile Ser Ser Ser Asn Trp Tyr Ser
1 5 10
<210> 136
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 136
Ala Ile Tyr His Ser Gly Asn Thr Asn Tyr Asn
1 5 10
<210> 137
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 137
Glu Ala Tyr His Ser Gly Asn Thr Asn Tyr Asn
1 5 10
<210> 138
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 138
Glu Ile Ala His Ser Gly Asn Thr Asn Tyr Asn
1 5 10
<210> 139
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 139
Glu Ile Tyr Ala Ser Gly Asn Thr Asn Tyr Asn
1 5 10
<210> 140
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 140
Glu Ile Tyr His Ala Gly Asn Thr Asn Tyr Asn
1 5 10
<210> 141
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 141
Glu Ile Tyr His Ser Ala Asn Thr Asn Tyr Asn
1 5 10
<210> 142
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 142
Glu Ile Tyr His Ser Gly Ala Thr Asn Tyr Asn
1 5 10
<210> 143
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 143
Glu Ile Tyr His Ser Gly Asn Ala Asn Tyr Asn
1 5 10
<210> 144
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 144
Glu Ile Tyr His Ser Gly Asn Thr Ala Tyr Asn
1 5 10
<210> 145
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 145
Glu Ile Tyr His Ser Gly Asn Thr Asn Ala Asn
1 5 10
<210> 146
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 146
Glu Ile Tyr His Ser Gly Asn Thr Asn Tyr Ala
1 5 10
<210> 147
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 147
Asp Ile Tyr His Ser Gly Asn Thr Asn Tyr Asn
1 5 10
<210> 148
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 148
Glu Ile Asp His Ser Gly Asn Thr Asn Tyr Asn
1 5 10
<210> 149
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 149
Glu Ile Tyr Asp Ser Gly Asn Thr Asn Tyr Asn
1 5 10
<210> 150
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 150
Glu Ile Tyr His Asp Gly Asn Thr Asn Tyr Asn
1 5 10
<210> 151
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 151
Glu Ile Tyr His Ser Gly Asp Thr Asn Tyr Asn
1 5 10
<210> 152
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 152
Glu Ile Tyr His Ser Gly Asn Asp Asn Tyr Asn
1 5 10
<210> 153
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 153
Glu Ile Tyr His Ser Gly Asn Thr Asp Tyr Asn
1 5 10
<210> 154
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 154
Glu Ile Tyr His Ser Gly Asn Thr Asn Asp Asn
1 5 10
<210> 155
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 155
Glu Ile Tyr His Ser Gly Asn Thr Asn Tyr Asp
1 5 10
<210> 156
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 156
His Ile Tyr His Ser Gly Asn Thr Asn Tyr Asn
1 5 10
<210> 157
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 157
Glu His Tyr His Ser Gly Asn Thr Asn Tyr Asn
1 5 10
<210> 158
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 158
Glu Ile His His Ser Gly Asn Thr Asn Tyr Asn
1 5 10
<210> 159
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 159
Glu Ile Tyr His His Gly Asn Thr Asn Tyr Asn
1 5 10
<210> 160
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 160
Glu Ile Tyr His Ser His Asn Thr Asn Tyr Asn
1 5 10
<210> 161
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 161
Glu Ile Tyr His Ser Gly His Thr Asn Tyr Asn
1 5 10
<210> 162
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 162
Glu Ile Tyr His Ser Gly Asn His Asn Tyr Asn
1 5 10
<210> 163
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 163
Glu Ile Tyr His Ser Gly Asn Thr His Tyr Asn
1 5 10
<210> 164
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 164
Glu Ile Tyr His Ser Gly Asn Thr Asn His Asn
1 5 10
<210> 165
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 165
Glu Ile Tyr His Ser Gly Asn Thr Asn Tyr His
1 5 10
<210> 166
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 166
Glu Lys Tyr His Ser Gly Asn Thr Asn Tyr Asn
1 5 10
<210> 167
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 167
Glu Ile Lys His Ser Gly Asn Thr Asn Tyr Asn
1 5 10
<210> 168
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 168
Glu Ile Tyr Lys Ser Gly Asn Thr Asn Tyr Asn
1 5 10
<210> 169
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 169
Glu Ile Tyr His Lys Gly Asn Thr Asn Tyr Asn
1 5 10
<210> 170
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 170
Glu Ile Tyr His Ser Lys Asn Thr Asn Tyr Asn
1 5 10
<210> 171
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 171
Glu Ile Tyr His Ser Gly Lys Thr Asn Tyr Asn
1 5 10
<210> 172
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 172
Glu Ile Tyr His Ser Gly Asn Lys Asn Tyr Asn
1 5 10
<210> 173
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 173
Glu Ile Tyr His Ser Gly Asn Thr Lys Tyr Asn
1 5 10
<210> 174
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 174
Glu Ile Tyr His Ser Gly Asn Thr Asn Lys Asn
1 5 10
<210> 175
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 175
Glu Ile Tyr His Ser Gly Asn Thr Asn Tyr Lys
1 5 10
<210> 176
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 176
Leu Ile Tyr His Ser Gly Asn Thr Asn Tyr Asn
1 5 10
<210> 177
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 177
Glu Leu Tyr His Ser Gly Asn Thr Asn Tyr Asn
1 5 10
<210> 178
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 178
Glu Ile Leu His Ser Gly Asn Thr Asn Tyr Asn
1 5 10
<210> 179
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 179
Glu Ile Tyr Leu Ser Gly Asn Thr Asn Tyr Asn
1 5 10
<210> 180
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 180
Glu Ile Tyr His Leu Gly Asn Thr Asn Tyr Asn
1 5 10
<210> 181
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 181
Glu Ile Tyr His Ser Leu Asn Thr Asn Tyr Asn
1 5 10
<210> 182
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 182
Glu Ile Tyr His Ser Gly Leu Thr Asn Tyr Asn
1 5 10
<210> 183
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 183
Glu Ile Tyr His Ser Gly Asn Leu Asn Tyr Asn
1 5 10
<210> 184
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 184
Glu Ile Tyr His Ser Gly Asn Thr Leu Tyr Asn
1 5 10
<210> 185
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 185
Glu Ile Tyr His Ser Gly Asn Thr Asn Leu Asn
1 5 10
<210> 186
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 186
Glu Ile Tyr His Ser Gly Asn Thr Asn Tyr Leu
1 5 10
<210> 187
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 187
Gln Ile Tyr His Ser Gly Asn Thr Asn Tyr Asn
1 5 10
<210> 188
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 188
Glu Gln Tyr His Ser Gly Asn Thr Asn Tyr Asn
1 5 10
<210> 189
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 189
Glu Ile Gln His Ser Gly Asn Thr Asn Tyr Asn
1 5 10
<210> 190
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 190
Glu Ile Tyr Gln Ser Gly Asn Thr Asn Tyr Asn
1 5 10
<210> 191
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 191
Glu Ile Tyr His Gln Gly Asn Thr Asn Tyr Asn
1 5 10
<210> 192
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 192
Glu Ile Tyr His Ser Gln Asn Thr Asn Tyr Asn
1 5 10
<210> 193
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 193
Glu Ile Tyr His Ser Gly Gln Thr Asn Tyr Asn
1 5 10
<210> 194
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 194
Glu Ile Tyr His Ser Gly Asn Gln Asn Tyr Asn
1 5 10
<210> 195
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 195
Glu Ile Tyr His Ser Gly Asn Thr Gln Tyr Asn
1 5 10
<210> 196
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 196
Glu Ile Tyr His Ser Gly Asn Thr Asn Gln Asn
1 5 10
<210> 197
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 197
Glu Ile Tyr His Ser Gly Asn Thr Asn Tyr Gln
1 5 10
<210> 198
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 198
Ser Ile Tyr His Ser Gly Asn Thr Asn Tyr Asn
1 5 10
<210> 199
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 199
Glu Ser Tyr His Ser Gly Asn Thr Asn Tyr Asn
1 5 10
<210> 200
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 200
Glu Ile Ser His Ser Gly Asn Thr Asn Tyr Asn
1 5 10
<210> 201
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 201
Glu Ile Tyr Ser Ser Gly Asn Thr Asn Tyr Asn
1 5 10
<210> 202
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 202
Glu Ile Tyr His Ser Ser Asn Thr Asn Tyr Asn
1 5 10
<210> 203
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 203
Glu Ile Tyr His Ser Gly Ser Thr Asn Tyr Asn
1 5 10
<210> 204
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 204
Glu Ile Tyr His Ser Gly Asn Ser Asn Tyr Asn
1 5 10
<210> 205
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 205
Glu Ile Tyr His Ser Gly Asn Thr Ser Tyr Asn
1 5 10
<210> 206
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 206
Glu Ile Tyr His Ser Gly Asn Thr Asn Ser Asn
1 5 10
<210> 207
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 207
Glu Ile Tyr His Ser Gly Asn Thr Asn Tyr Ser
1 5 10
<210> 208
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 208
Trp Ile Tyr His Ser Gly Asn Thr Asn Tyr Asn
1 5 10
<210> 209
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 209
Glu Ile Trp His Ser Gly Asn Thr Asn Tyr Asn
1 5 10
<210> 210
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 210
Glu Ile Tyr Trp Ser Gly Asn Thr Asn Tyr Asn
1 5 10
<210> 211
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 211
Glu Ile Tyr His Trp Gly Asn Thr Asn Tyr Asn
1 5 10
<210> 212
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 212
Glu Ile Tyr His Ser Trp Asn Thr Asn Tyr Asn
1 5 10
<210> 213
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 213
Glu Ile Tyr His Ser Gly Trp Thr Asn Tyr Asn
1 5 10
<210> 214
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 214
Glu Ile Tyr His Ser Gly Asn Trp Asn Tyr Asn
1 5 10
<210> 215
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 215
Glu Ile Tyr His Ser Gly Asn Thr Trp Tyr Asn
1 5 10
<210> 216
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 216
Glu Ile Tyr His Ser Gly Asn Thr Asn Trp Asn
1 5 10
<210> 217
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 217
Glu Ile Tyr His Ser Gly Asn Thr Asn Tyr Trp
1 5 10
<210> 218
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 218
Tyr Ile Tyr His Ser Gly Asn Thr Asn Tyr Asn
1 5 10
<210> 219
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 219
Glu Tyr Tyr His Ser Gly Asn Thr Asn Tyr Asn
1 5 10
<210> 220
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 220
Glu Ile Tyr Tyr Ser Gly Asn Thr Asn Tyr Asn
1 5 10
<210> 221
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 221
Glu Ile Tyr His Tyr Gly Asn Thr Asn Tyr Asn
1 5 10
<210> 222
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 222
Glu Ile Tyr His Ser Tyr Asn Thr Asn Tyr Asn
1 5 10
<210> 223
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 223
Glu Ile Tyr His Ser Gly Tyr Thr Asn Tyr Asn
1 5 10
<210> 224
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 224
Glu Ile Tyr His Ser Gly Asn Tyr Asn Tyr Asn
1 5 10
<210> 225
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 225
Glu Ile Tyr His Ser Gly Asn Thr Tyr Tyr Asn
1 5 10
<210> 226
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 226
Glu Ile Tyr His Ser Gly Asn Thr Asn Tyr Tyr
1 5 10
<210> 227
<211> 10
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 227
Ala Gly Ile Gly Trp Pro Ser Phe Asp Tyr
1 5 10
<210> 228
<211> 10
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 228
Glu Ala Ile Gly Trp Pro Ser Phe Asp Tyr
1 5 10
<210> 229
<211> 10
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 229
Glu Gly Ala Gly Trp Pro Ser Phe Asp Tyr
1 5 10
<210> 230
<211> 10
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 230
Glu Gly Ile Ala Trp Pro Ser Phe Asp Tyr
1 5 10
<210> 231
<211> 10
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 231
Glu Gly Ile Gly Trp Pro Ala Phe Asp Tyr
1 5 10
<210> 232
<211> 10
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 232
Glu Gly Ile Gly Trp Pro Ser Phe Asp Ala
1 5 10
<210> 233
<211> 10
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 233
Asp Gly Ile Gly Trp Pro Ser Phe Asp Tyr
1 5 10
<210> 234
<211> 10
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 234
Glu Asp Ile Gly Trp Pro Ser Phe Asp Tyr
1 5 10
<210> 235
<211> 10
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 235
Glu Gly Asp Gly Trp Pro Ser Phe Asp Tyr
1 5 10
<210> 236
<211> 10
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 236
Glu Gly Ile Gly Trp Pro Ser Phe Asp Asp
1 5 10
<210> 237
<211> 10
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 237
His Gly Ile Gly Trp Pro Ser Phe Asp Tyr
1 5 10
<210> 238
<211> 10
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 238
Glu His Ile Gly Trp Pro Ser Phe Asp Tyr
1 5 10
<210> 239
<211> 10
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 239
Glu Gly His Gly Trp Pro Ser Phe Asp Tyr
1 5 10
<210> 240
<211> 10
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 240
Glu Gly Ile Gly Trp Pro His Phe Asp Tyr
1 5 10
<210> 241
<211> 10
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 241
Glu Gly Ile Gly Trp Pro Ser His Asp Tyr
1 5 10
<210> 242
<211> 10
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 242
Glu Gly Ile Gly Trp Pro Ser Phe Asp His
1 5 10
<210> 243
<211> 10
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 243
Glu Lys Ile Gly Trp Pro Ser Phe Asp Tyr
1 5 10
<210> 244
<211> 10
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 244
Glu Gly Lys Gly Trp Pro Ser Phe Asp Tyr
1 5 10
<210> 245
<211> 10
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 245
Glu Gly Ile Gly Trp Pro Ser Phe Lys Tyr
1 5 10
<210> 246
<211> 10
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 246
Glu Gly Ile Gly Trp Pro Ser Phe Asp Lys
1 5 10
<210> 247
<211> 10
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 247
Leu Gly Ile Gly Trp Pro Ser Phe Asp Tyr
1 5 10
<210> 248
<211> 10
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 248
Glu Gly Leu Gly Trp Pro Ser Phe Asp Tyr
1 5 10
<210> 249
<211> 10
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 249
Glu Gly Ile Gly Trp Pro Leu Phe Asp Tyr
1 5 10
<210> 250
<211> 10
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 250
Glu Gly Ile Gly Trp Pro Ser Leu Asp Tyr
1 5 10
<210> 251
<211> 10
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 251
Glu Gly Ile Gly Trp Pro Ser Phe Asp Leu
1 5 10
<210> 252
<211> 10
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 252
Gln Gly Ile Gly Trp Pro Ser Phe Asp Tyr
1 5 10
<210> 253
<211> 10
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 253
Glu Gln Ile Gly Trp Pro Ser Phe Asp Tyr
1 5 10
<210> 254
<211> 10
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 254
Glu Gly Gln Gly Trp Pro Ser Phe Asp Tyr
1 5 10
<210> 255
<211> 10
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 255
Glu Gly Ile Gly Trp Pro Gln Phe Asp Tyr
1 5 10
<210> 256
<211> 10
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 256
Glu Gly Ile Gly Trp Pro Ser Phe Gln Tyr
1 5 10
<210> 257
<211> 10
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 257
Glu Gly Ile Gly Trp Pro Ser Phe Asp Gln
1 5 10
<210> 258
<211> 10
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 258
Ser Gly Ile Gly Trp Pro Ser Phe Asp Tyr
1 5 10
<210> 259
<211> 10
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 259
Glu Ser Ile Gly Trp Pro Ser Phe Asp Tyr
1 5 10
<210> 260
<211> 10
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 260
Glu Gly Ser Gly Trp Pro Ser Phe Asp Tyr
1 5 10
<210> 261
<211> 10
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 261
Glu Gly Ile Gly Trp Pro Ser Phe Asp Ser
1 5 10
<210> 262
<211> 10
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 262
Glu Trp Ile Gly Trp Pro Ser Phe Asp Tyr
1 5 10
<210> 263
<211> 10
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 263
Glu Gly Trp Gly Trp Pro Ser Phe Asp Tyr
1 5 10
<210> 264
<211> 10
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 264
Glu Gly Ile Gly Trp Pro Trp Phe Asp Tyr
1 5 10
<210> 265
<211> 10
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 265
Glu Gly Ile Gly Trp Pro Ser Trp Asp Tyr
1 5 10
<210> 266
<211> 10
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 266
Glu Gly Ile Gly Trp Pro Ser Phe Asp Trp
1 5 10
<210> 267
<211> 10
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 267
Glu Tyr Ile Gly Trp Pro Ser Phe Asp Tyr
1 5 10
<210> 268
<211> 10
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 268
Glu Gly Tyr Gly Trp Pro Ser Phe Asp Tyr
1 5 10
<210> 269
<211> 10
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 269
Glu Gly Ile Gly Tyr Pro Ser Phe Asp Tyr
1 5 10
<210> 270
<211> 10
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 270
Glu Gly Ile Gly Trp Pro Tyr Phe Asp Tyr
1 5 10
<210> 271
<211> 10
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 271
Glu Gly Ile Gly Trp Pro Ser Tyr Asp Tyr
1 5 10
<210> 272
<211> 10
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 272
Glu Gly Ile Gly Trp Pro Ser Phe Tyr Tyr
1 5 10
<210> 273
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 273
Ala Gly Asp Thr Leu Arg Asn Tyr Tyr Ala Ser
1 5 10
<210> 274
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 274
Gln Ala Asp Thr Leu Arg Asn Tyr Tyr Ala Ser
1 5 10
<210> 275
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 275
Gln Gly Ala Thr Leu Arg Asn Tyr Tyr Ala Ser
1 5 10
<210> 276
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 276
Gln Gly Asp Ala Leu Arg Asn Tyr Tyr Ala Ser
1 5 10
<210> 277
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 277
Gln Gly Asp Thr Ala Arg Asn Tyr Tyr Ala Ser
1 5 10
<210> 278
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 278
Gln Gly Asp Thr Leu Ala Asn Tyr Tyr Ala Ser
1 5 10
<210> 279
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 279
Gln Gly Asp Thr Leu Arg Ala Tyr Tyr Ala Ser
1 5 10
<210> 280
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 280
Gln Gly Asp Thr Leu Arg Asn Tyr Ala Ala Ser
1 5 10
<210> 281
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 281
Gln Gly Asp Thr Leu Arg Asn Tyr Tyr Ala Ala
1 5 10
<210> 282
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 282
Asp Gly Asp Thr Leu Arg Asn Tyr Tyr Ala Ser
1 5 10
<210> 283
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 283
Gln Asp Asp Thr Leu Arg Asn Tyr Tyr Ala Ser
1 5 10
<210> 284
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 284
Gln Gly Asp Asp Leu Arg Asn Tyr Tyr Ala Ser
1 5 10
<210> 285
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 285
Gln Gly Asp Thr Leu Asp Asn Tyr Tyr Ala Ser
1 5 10
<210> 286
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 286
Gln Gly Asp Thr Leu Arg Asp Tyr Tyr Ala Ser
1 5 10
<210> 287
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 287
His Gly Asp Thr Leu Arg Asn Tyr Tyr Ala Ser
1 5 10
<210> 288
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 288
Gln His Asp Thr Leu Arg Asn Tyr Tyr Ala Ser
1 5 10
<210> 289
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 289
Gln Gly His Thr Leu Arg Asn Tyr Tyr Ala Ser
1 5 10
<210> 290
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 290
Gln Gly Asp His Leu Arg Asn Tyr Tyr Ala Ser
1 5 10
<210> 291
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 291
Gln Gly Asp Thr His Arg Asn Tyr Tyr Ala Ser
1 5 10
<210> 292
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 292
Gln Gly Asp Thr Leu His Asn Tyr Tyr Ala Ser
1 5 10
<210> 293
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 293
Gln Gly Asp Thr Leu Arg His Tyr Tyr Ala Ser
1 5 10
<210> 294
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 294
Gln Gly Asp Thr Leu Arg Asn Tyr His Ala Ser
1 5 10
<210> 295
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 295
Lys Gly Asp Thr Leu Arg Asn Tyr Tyr Ala Ser
1 5 10
<210> 296
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 296
Gln Lys Asp Thr Leu Arg Asn Tyr Tyr Ala Ser
1 5 10
<210> 297
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 297
Gln Gly Lys Thr Leu Arg Asn Tyr Tyr Ala Ser
1 5 10
<210> 298
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 298
Gln Gly Asp Thr Leu Lys Asn Tyr Tyr Ala Ser
1 5 10
<210> 299
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 299
Gln Gly Asp Thr Leu Arg Lys Tyr Tyr Ala Ser
1 5 10
<210> 300
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 300
Leu Gly Asp Thr Leu Arg Asn Tyr Tyr Ala Ser
1 5 10
<210> 301
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 301
Gln Gly Leu Thr Leu Arg Asn Tyr Tyr Ala Ser
1 5 10
<210> 302
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 302
Gln Gly Asp Leu Leu Arg Asn Tyr Tyr Ala Ser
1 5 10
<210> 303
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 303
Gln Gly Asp Thr Leu Leu Asn Tyr Tyr Ala Ser
1 5 10
<210> 304
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 304
Gln Gly Asp Thr Leu Arg Leu Tyr Tyr Ala Ser
1 5 10
<210> 305
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 305
Gln Gly Asp Thr Leu Arg Asn Tyr Leu Ala Ser
1 5 10
<210> 306
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 306
Gln Gln Asp Thr Leu Arg Asn Tyr Tyr Ala Ser
1 5 10
<210> 307
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 307
Gln Gly Gln Thr Leu Arg Asn Tyr Tyr Ala Ser
1 5 10
<210> 308
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 308
Gln Gly Asp Gln Leu Arg Asn Tyr Tyr Ala Ser
1 5 10
<210> 309
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 309
Gln Gly Asp Thr Leu Gln Asn Tyr Tyr Ala Ser
1 5 10
<210> 310
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 310
Gln Gly Asp Thr Leu Arg Gln Tyr Tyr Ala Ser
1 5 10
<210> 311
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 311
Gln Gly Asp Thr Leu Arg Asn Tyr Gln Ala Ser
1 5 10
<210> 312
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 312
Ser Gly Asp Thr Leu Arg Asn Tyr Tyr Ala Ser
1 5 10
<210> 313
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 313
Gln Ser Asp Thr Leu Arg Asn Tyr Tyr Ala Ser
1 5 10
<210> 314
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 314
Gln Gly Ser Thr Leu Arg Asn Tyr Tyr Ala Ser
1 5 10
<210> 315
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 315
Gln Gly Asp Ser Leu Arg Asn Tyr Tyr Ala Ser
1 5 10
<210> 316
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 316
Gln Gly Asp Thr Leu Ser Asn Tyr Tyr Ala Ser
1 5 10
<210> 317
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 317
Gln Gly Asp Thr Leu Arg Ser Tyr Tyr Ala Ser
1 5 10
<210> 318
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 318
Trp Gly Asp Thr Leu Arg Asn Tyr Tyr Ala Ser
1 5 10
<210> 319
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 319
Gln Gly Trp Thr Leu Arg Asn Tyr Tyr Ala Ser
1 5 10
<210> 320
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 320
Gln Gly Asp Trp Leu Arg Asn Tyr Tyr Ala Ser
1 5 10
<210> 321
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 321
Gln Gly Asp Thr Leu Trp Asn Tyr Tyr Ala Ser
1 5 10
<210> 322
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 322
Gln Gly Asp Thr Leu Arg Trp Tyr Tyr Ala Ser
1 5 10
<210> 323
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 323
Gln Gly Asp Thr Leu Arg Asn Trp Tyr Ala Ser
1 5 10
<210> 324
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 324
Gln Gly Asp Thr Leu Arg Asn Tyr Trp Ala Ser
1 5 10
<210> 325
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 325
Tyr Gly Asp Thr Leu Arg Asn Tyr Tyr Ala Ser
1 5 10
<210> 326
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 326
Gln Gly Tyr Thr Leu Arg Asn Tyr Tyr Ala Ser
1 5 10
<210> 327
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 327
Gln Gly Asp Tyr Leu Arg Asn Tyr Tyr Ala Ser
1 5 10
<210> 328
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 328
Gln Gly Asp Thr Leu Tyr Asn Tyr Tyr Ala Ser
1 5 10
<210> 329
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 329
Gln Gly Asp Thr Leu Arg Tyr Tyr Tyr Ala Ser
1 5 10
<210> 330
<211> 7
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 330
Ala Lys Asn Asn Arg Pro Ser
1 5
<210> 331
<211> 7
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 331
Gly Ala Asn Asn Arg Pro Ser
1 5
<210> 332
<211> 7
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 332
Gly Lys Ala Asn Arg Pro Ser
1 5
<210> 333
<211> 7
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 333
Gly Lys Asn Ala Arg Pro Ser
1 5
<210> 334
<211> 7
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 334
Gly Lys Asn Asn Ala Pro Ser
1 5
<210> 335
<211> 7
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 335
Gly Lys Asn Asn Arg Ala Ser
1 5
<210> 336
<211> 7
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 336
Gly Lys Asn Asn Arg Pro Ala
1 5
<210> 337
<211> 7
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 337
Asp Lys Asn Asn Arg Pro Ser
1 5
<210> 338
<211> 7
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 338
Gly Asp Asn Asn Arg Pro Ser
1 5
<210> 339
<211> 7
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 339
Gly Lys Asp Asn Arg Pro Ser
1 5
<210> 340
<211> 7
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 340
Gly Lys Asn Asp Arg Pro Ser
1 5
<210> 341
<211> 7
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 341
Gly Lys Asn Asn Asp Pro Ser
1 5
<210> 342
<211> 7
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 342
Gly Lys Asn Asn Arg Asp Ser
1 5
<210> 343
<211> 7
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 343
Gly Lys Asn Asn Arg Pro Asp
1 5
<210> 344
<211> 7
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 344
His Lys Asn Asn Arg Pro Ser
1 5
<210> 345
<211> 7
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 345
Gly His Asn Asn Arg Pro Ser
1 5
<210> 346
<211> 7
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 346
Gly Lys His Asn Arg Pro Ser
1 5
<210> 347
<211> 7
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 347
Gly Lys Asn His Arg Pro Ser
1 5
<210> 348
<211> 7
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 348
Gly Lys Asn Asn His Pro Ser
1 5
<210> 349
<211> 7
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 349
Gly Lys Asn Asn Arg His Ser
1 5
<210> 350
<211> 7
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 350
Gly Lys Asn Asn Arg Pro His
1 5
<210> 351
<211> 7
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 351
Lys Lys Asn Asn Arg Pro Ser
1 5
<210> 352
<211> 7
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 352
Gly Lys Lys Asn Arg Pro Ser
1 5
<210> 353
<211> 7
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 353
Gly Lys Asn Lys Arg Pro Ser
1 5
<210> 354
<211> 7
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 354
Gly Lys Asn Asn Lys Pro Ser
1 5
<210> 355
<211> 7
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 355
Gly Lys Asn Asn Arg Lys Ser
1 5
<210> 356
<211> 7
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 356
Gly Lys Asn Asn Arg Pro Lys
1 5
<210> 357
<211> 7
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 357
Leu Lys Asn Asn Arg Pro Ser
1 5
<210> 358
<211> 7
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 358
Gly Leu Asn Asn Arg Pro Ser
1 5
<210> 359
<211> 7
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 359
Gly Lys Leu Asn Arg Pro Ser
1 5
<210> 360
<211> 7
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 360
Gly Lys Asn Leu Arg Pro Ser
1 5
<210> 361
<211> 7
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 361
Gly Lys Asn Asn Leu Pro Ser
1 5
<210> 362
<211> 7
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 362
Gly Lys Asn Asn Arg Leu Ser
1 5
<210> 363
<211> 7
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 363
Gly Lys Asn Asn Arg Pro Leu
1 5
<210> 364
<211> 7
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 364
Gln Lys Asn Asn Arg Pro Ser
1 5
<210> 365
<211> 7
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 365
Gly Gln Asn Asn Arg Pro Ser
1 5
<210> 366
<211> 7
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 366
Gly Lys Gln Asn Arg Pro Ser
1 5
<210> 367
<211> 7
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 367
Gly Lys Asn Gln Arg Pro Ser
1 5
<210> 368
<211> 7
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 368
Gly Lys Asn Asn Gln Pro Ser
1 5
<210> 369
<211> 7
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 369
Gly Lys Asn Asn Arg Gln Ser
1 5
<210> 370
<211> 7
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 370
Gly Lys Asn Asn Arg Pro Gln
1 5
<210> 371
<211> 7
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 371
Ser Lys Asn Asn Arg Pro Ser
1 5
<210> 372
<211> 7
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 372
Gly Ser Asn Asn Arg Pro Ser
1 5
<210> 373
<211> 7
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 373
Gly Lys Ser Asn Arg Pro Ser
1 5
<210> 374
<211> 7
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 374
Gly Lys Asn Ser Arg Pro Ser
1 5
<210> 375
<211> 7
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 375
Gly Lys Asn Asn Ser Pro Ser
1 5
<210> 376
<211> 7
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 376
Gly Lys Asn Asn Arg Ser Ser
1 5
<210> 377
<211> 7
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 377
Trp Lys Asn Asn Arg Pro Ser
1 5
<210> 378
<211> 7
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 378
Gly Trp Asn Asn Arg Pro Ser
1 5
<210> 379
<211> 7
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 379
Gly Lys Trp Asn Arg Pro Ser
1 5
<210> 380
<211> 7
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 380
Gly Lys Asn Trp Arg Pro Ser
1 5
<210> 381
<211> 7
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 381
Gly Lys Asn Asn Trp Pro Ser
1 5
<210> 382
<211> 7
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 382
Gly Lys Asn Asn Arg Trp Ser
1 5
<210> 383
<211> 7
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 383
Gly Lys Asn Asn Arg Pro Trp
1 5
<210> 384
<211> 7
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 384
Tyr Lys Asn Asn Arg Pro Ser
1 5
<210> 385
<211> 7
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 385
Gly Tyr Asn Asn Arg Pro Ser
1 5
<210> 386
<211> 7
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 386
Gly Lys Tyr Asn Arg Pro Ser
1 5
<210> 387
<211> 7
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 387
Gly Lys Asn Tyr Arg Pro Ser
1 5
<210> 388
<211> 7
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 388
Gly Lys Asn Asn Tyr Pro Ser
1 5
<210> 389
<211> 7
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 389
Gly Lys Asn Asn Arg Tyr Ser
1 5
<210> 390
<211> 7
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 390
Gly Lys Asn Asn Arg Pro Tyr
1 5
<210> 391
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 391
Asn Ala Arg Asp Ser Ser Gly Lys Asn Leu Val
1 5 10
<210> 392
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 392
Asn Ser Arg Asp Ala Ser Gly Lys Asn Leu Val
1 5 10
<210> 393
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 393
Asn Ser Arg Asp Ser Ala Gly Lys Asn Leu Val
1 5 10
<210> 394
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 394
Asn Ser Arg Asp Ser Ser Ala Lys Asn Leu Val
1 5 10
<210> 395
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 395
Asn Ser Arg Asp Ser Ser Gly Ala Asn Leu Val
1 5 10
<210> 396
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 396
Asn Ser Arg Asp Ser Ser Gly Lys Ala Leu Val
1 5 10
<210> 397
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 397
Asn Ser Arg Asp Ser Ser Gly Lys Asn Ala Val
1 5 10
<210> 398
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 398
Asn Ser Arg Asp Ser Ser Gly Lys Asn Leu Ala
1 5 10
<210> 399
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 399
Asp Ser Arg Asp Ser Ser Gly Lys Asn Leu Val
1 5 10
<210> 400
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 400
Asn Asp Arg Asp Ser Ser Gly Lys Asn Leu Val
1 5 10
<210> 401
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 401
Asn Ser Arg Asp Asp Ser Gly Lys Asn Leu Val
1 5 10
<210> 402
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 402
Asn Ser Arg Asp Ser Asp Gly Lys Asn Leu Val
1 5 10
<210> 403
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 403
Asn Ser Arg Asp Ser Ser Gly Asp Asn Leu Val
1 5 10
<210> 404
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 404
Asn Ser Arg Asp Ser Ser Gly Lys Asp Leu Val
1 5 10
<210> 405
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 405
Asn Ser Arg Asp Ser Ser Gly Lys Asn Leu Asp
1 5 10
<210> 406
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 406
His Ser Arg Asp Ser Ser Gly Lys Asn Leu Val
1 5 10
<210> 407
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 407
Asn Ser Arg Asp His Ser Gly Lys Asn Leu Val
1 5 10
<210> 408
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 408
Asn Ser Arg Asp Ser His Gly Lys Asn Leu Val
1 5 10
<210> 409
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 409
Asn Ser Arg Asp Ser Ser Gly His Asn Leu Val
1 5 10
<210> 410
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 410
Asn Ser Arg Asp Ser Ser Gly Lys His Leu Val
1 5 10
<210> 411
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 411
Asn Ser Arg Asp Ser Ser Gly Lys Asn His Val
1 5 10
<210> 412
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 412
Asn Ser Arg Asp Ser Ser Gly Lys Asn Leu His
1 5 10
<210> 413
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 413
Lys Ser Arg Asp Ser Ser Gly Lys Asn Leu Val
1 5 10
<210> 414
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 414
Asn Ser Lys Asp Ser Ser Gly Lys Asn Leu Val
1 5 10
<210> 415
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 415
Asn Ser Arg Asp Lys Ser Gly Lys Asn Leu Val
1 5 10
<210> 416
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 416
Asn Ser Arg Asp Ser Lys Gly Lys Asn Leu Val
1 5 10
<210> 417
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 417
Asn Ser Arg Asp Ser Ser Gly Lys Lys Leu Val
1 5 10
<210> 418
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 418
Asn Ser Arg Asp Ser Ser Gly Lys Asn Leu Lys
1 5 10
<210> 419
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 419
Leu Ser Arg Asp Ser Ser Gly Lys Asn Leu Val
1 5 10
<210> 420
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 420
Asn Ser Arg Asp Leu Ser Gly Lys Asn Leu Val
1 5 10
<210> 421
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 421
Asn Ser Arg Asp Ser Leu Gly Lys Asn Leu Val
1 5 10
<210> 422
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 422
Asn Ser Arg Asp Ser Ser Leu Lys Asn Leu Val
1 5 10
<210> 423
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 423
Asn Ser Arg Asp Ser Ser Gly Leu Asn Leu Val
1 5 10
<210> 424
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 424
Asn Ser Arg Asp Ser Ser Gly Lys Leu Leu Val
1 5 10
<210> 425
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 425
Asn Ser Arg Asp Ser Ser Gly Lys Asn Leu Leu
1 5 10
<210> 426
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 426
Gln Ser Arg Asp Ser Ser Gly Lys Asn Leu Val
1 5 10
<210> 427
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 427
Asn Ser Arg Asp Gln Ser Gly Lys Asn Leu Val
1 5 10
<210> 428
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 428
Asn Ser Arg Asp Ser Gln Gly Lys Asn Leu Val
1 5 10
<210> 429
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 429
Asn Ser Arg Asp Ser Ser Gly Gln Asn Leu Val
1 5 10
<210> 430
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 430
Asn Ser Arg Asp Ser Ser Gly Lys Gln Leu Val
1 5 10
<210> 431
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 431
Asn Ser Arg Asp Ser Ser Gly Lys Asn Gln Val
1 5 10
<210> 432
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 432
Asn Ser Arg Asp Ser Ser Gly Lys Asn Leu Gln
1 5 10
<210> 433
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 433
Ser Ser Arg Asp Ser Ser Gly Lys Asn Leu Val
1 5 10
<210> 434
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 434
Asn Ser Arg Asp Ser Ser Ser Lys Asn Leu Val
1 5 10
<210> 435
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 435
Asn Ser Arg Asp Ser Ser Gly Ser Asn Leu Val
1 5 10
<210> 436
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 436
Asn Ser Arg Asp Ser Ser Gly Lys Ser Leu Val
1 5 10
<210> 437
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 437
Asn Ser Arg Asp Ser Ser Gly Lys Asn Ser Val
1 5 10
<210> 438
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 438
Asn Ser Arg Asp Ser Ser Gly Lys Asn Leu Ser
1 5 10
<210> 439
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 439
Asn Ser Arg Asp Trp Ser Gly Lys Asn Leu Val
1 5 10
<210> 440
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 440
Asn Ser Arg Asp Ser Trp Gly Lys Asn Leu Val
1 5 10
<210> 441
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 441
Asn Ser Arg Asp Ser Ser Gly Trp Asn Leu Val
1 5 10
<210> 442
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 442
Asn Ser Arg Asp Ser Ser Gly Lys Trp Leu Val
1 5 10
<210> 443
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 443
Asn Ser Arg Asp Ser Ser Gly Lys Asn Trp Val
1 5 10
<210> 444
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 444
Asn Ser Arg Asp Ser Ser Gly Lys Asn Leu Trp
1 5 10
<210> 445
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 445
Tyr Ser Arg Asp Ser Ser Gly Lys Asn Leu Val
1 5 10
<210> 446
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 446
Asn Ser Arg Asp Tyr Ser Gly Lys Asn Leu Val
1 5 10
<210> 447
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 447
Asn Ser Arg Asp Ser Tyr Gly Lys Asn Leu Val
1 5 10
<210> 448
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 448
Asn Ser Arg Asp Ser Ser Tyr Lys Asn Leu Val
1 5 10
<210> 449
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 449
Asn Ser Arg Asp Ser Ser Gly Tyr Asn Leu Val
1 5 10
<210> 450
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 450
Asn Ser Arg Asp Ser Ser Gly Lys Tyr Leu Val
1 5 10
<210> 451
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 451
Asn Ser Arg Asp Ser Ser Gly Lys Asn Tyr Val
1 5 10
<210> 452
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 452
Asn Ser Arg Asp Ser Ser Gly Lys Asn Leu Tyr
1 5 10
<210> 453
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 453
Gly Gly Ser Ile Ser Ser Ser Asn Trp Trp Ser
1 5 10
<210> 454
<211> 119
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 454
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gly
1 5 10 15
Thr Leu Ser Leu Thr Cys Ala Val Ser Gly Gly Ser Ile Ser Ser Ser
20 25 30
Asn Trp Trp Ser Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp
35 40 45
Ile Gly Glu Ile Tyr His Tyr Gly Tyr Thr Asn Tyr Asn Pro Ser Leu
50 55 60
Lys Ser Arg Val Thr Ile Ser Val Asp Lys Ser Lys Asn Gln Phe Ser
65 70 75 80
Leu Lys Leu Ile Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Glu Gly Ile Gly Trp Pro Ser Phe Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 455
<211> 108
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 455
Ser Ser Glu Leu Thr Gln Asp Pro Ala Ala Ser Val Ala Leu Gly Gln
1 5 10 15
Thr Val Arg Ile Thr Cys Gln Gly Asp Thr Leu Arg Ser Tyr Tyr Ala
20 25 30
Ser Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Ile Leu Val Ile Tyr
35 40 45
Gly Lys Asn Asn Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser Gly Ser
50 55 60
Ser Ser Gly Asn Thr Ala Ser Leu Thr Ile Thr Gly Ala Gln Ala Glu
65 70 75 80
Asp Glu Ala Asp Tyr Tyr Cys Asn Ser Arg Asp Ser Ser Gly Lys Asn
85 90 95
Leu Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
100 105
<210> 456
<211> 214
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 456
Ser Ser Glu Leu Thr Gln Asp Pro Ala Ala Ser Val Ala Leu Gly Gln
1 5 10 15
Thr Val Arg Ile Thr Cys Gln Gly Asp Thr Leu Arg Ser Tyr Tyr Ala
20 25 30
Ser Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Ile Leu Val Ile Tyr
35 40 45
Gly Lys Asn Asn Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser Gly Ser
50 55 60
Ser Ser Gly Asn Thr Ala Ser Leu Thr Ile Thr Gly Ala Gln Ala Glu
65 70 75 80
Asp Glu Ala Asp Tyr Tyr Cys Asn Ser Arg Asp Ser Ser Gly Lys Asn
85 90 95
Leu Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gln Pro Lys
100 105 110
Ala Ala Pro Ser Val Thr Leu Phe Pro Pro Ser Ser Glu Glu Leu Gln
115 120 125
Ala Asn Lys Ala Thr Leu Val Cys Leu Ile Ser Asp Phe Tyr Pro Gly
130 135 140
Ala Val Thr Val Ala Trp Lys Ala Asp Ser Ser Pro Val Lys Ala Gly
145 150 155 160
Val Glu Thr Thr Thr Pro Ser Lys Gln Ser Asn Asn Lys Tyr Ala Ala
165 170 175
Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys Ser His Arg Ser
180 185 190
Tyr Ser Cys Gln Val Thr His Glu Gly Ser Thr Val Glu Lys Thr Val
195 200 205
Ala Pro Thr Glu Cys Ser
210
<210> 457
<211> 108
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 457
Ser Ser Glu Leu Thr Gln Asp Pro Ala Ala Ser Val Ala Leu Gly Gln
1 5 10 15
Thr Val Arg Ile Thr Cys Gln Gly Asp Thr Leu Arg Asn Tyr Tyr Ala
20 25 30
Ser Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Ile Leu Val Ile Tyr
35 40 45
Gly Lys Asn Asn Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser Gly Ser
50 55 60
Ser Ser Gly Asn Thr Ala Ser Leu Thr Ile Thr Gly Ala Gln Ala Glu
65 70 75 80
Asp Glu Ala Asp Tyr Tyr Cys Asn Ser Arg Asp Leu Ser Gly Lys Asn
85 90 95
Leu Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
100 105
<210> 458
<211> 214
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 458
Ser Ser Glu Leu Thr Gln Asp Pro Ala Ala Ser Val Ala Leu Gly Gln
1 5 10 15
Thr Val Arg Ile Thr Cys Gln Gly Asp Thr Leu Arg Asn Tyr Tyr Ala
20 25 30
Ser Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Ile Leu Val Ile Tyr
35 40 45
Gly Lys Asn Asn Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser Gly Ser
50 55 60
Ser Ser Gly Asn Thr Ala Ser Leu Thr Ile Thr Gly Ala Gln Ala Glu
65 70 75 80
Asp Glu Ala Asp Tyr Tyr Cys Asn Ser Arg Asp Leu Ser Gly Lys Asn
85 90 95
Leu Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gln Pro Lys
100 105 110
Ala Ala Pro Ser Val Thr Leu Phe Pro Pro Ser Ser Glu Glu Leu Gln
115 120 125
Ala Asn Lys Ala Thr Leu Val Cys Leu Ile Ser Asp Phe Tyr Pro Gly
130 135 140
Ala Val Thr Val Ala Trp Lys Ala Asp Ser Ser Pro Val Lys Ala Gly
145 150 155 160
Val Glu Thr Thr Thr Pro Ser Lys Gln Ser Asn Asn Lys Tyr Ala Ala
165 170 175
Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys Ser His Arg Ser
180 185 190
Tyr Ser Cys Gln Val Thr His Glu Gly Ser Thr Val Glu Lys Thr Val
195 200 205
Ala Pro Thr Glu Cys Ser
210
<210> 459
<211> 108
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 459
Ser Ser Glu Leu Thr Gln Asp Pro Ala Ala Ser Val Ala Leu Gly Gln
1 5 10 15
Thr Val Arg Ile Thr Cys Gln Gly Asp Thr Leu Arg Asn Tyr Tyr Ala
20 25 30
Ser Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Ile Leu Val Ile Tyr
35 40 45
Gly Lys Asn Asn Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser Gly Ser
50 55 60
Ser Ser Gly Asn Thr Ala Ser Leu Thr Ile Thr Gly Ala Gln Ala Glu
65 70 75 80
Asp Glu Ala Asp Tyr Tyr Cys Asn Ser Arg Asp Phe Ser Gly Lys Asn
85 90 95
Leu Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
100 105
<210> 460
<211> 214
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 460
Ser Ser Glu Leu Thr Gln Asp Pro Ala Ala Ser Val Ala Leu Gly Gln
1 5 10 15
Thr Val Arg Ile Thr Cys Gln Gly Asp Thr Leu Arg Asn Tyr Tyr Ala
20 25 30
Ser Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Ile Leu Val Ile Tyr
35 40 45
Gly Lys Asn Asn Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser Gly Ser
50 55 60
Ser Ser Gly Asn Thr Ala Ser Leu Thr Ile Thr Gly Ala Gln Ala Glu
65 70 75 80
Asp Glu Ala Asp Tyr Tyr Cys Asn Ser Arg Asp Phe Ser Gly Lys Asn
85 90 95
Leu Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gln Pro Lys
100 105 110
Ala Ala Pro Ser Val Thr Leu Phe Pro Pro Ser Ser Glu Glu Leu Gln
115 120 125
Ala Asn Lys Ala Thr Leu Val Cys Leu Ile Ser Asp Phe Tyr Pro Gly
130 135 140
Ala Val Thr Val Ala Trp Lys Ala Asp Ser Ser Pro Val Lys Ala Gly
145 150 155 160
Val Glu Thr Thr Thr Pro Ser Lys Gln Ser Asn Asn Lys Tyr Ala Ala
165 170 175
Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys Ser His Arg Ser
180 185 190
Tyr Ser Cys Gln Val Thr His Glu Gly Ser Thr Val Glu Lys Thr Val
195 200 205
Ala Pro Thr Glu Cys Ser
210
<210> 461
<211> 119
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 461
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gly
1 5 10 15
Thr Leu Ser Leu Thr Cys Ala Val Ser Gly Gly Ser Ile Ser Ser Ser
20 25 30
Asn Trp Trp Ser Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp
35 40 45
Ile Gly Glu Ile Tyr His Ser Gly Asn Thr Asn Tyr Asn Pro Ser Leu
50 55 60
Lys Ser Arg Val Thr Ile Ser Val Asp Lys Ser Lys Asn Gln Phe Ser
65 70 75 80
Leu Lys Leu Ile Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Glu Gly Ile Gly Trp Pro Ser Phe Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 462
<211> 119
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 462
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gly
1 5 10 15
Thr Leu Ser Leu Thr Cys Ala Val Ser Gly Gly Ser Ile Ser Ser Ser
20 25 30
Asn Trp Trp Ser Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp
35 40 45
Ile Gly Glu Ile Tyr His Phe Gly Asn Thr Asn Tyr Asn Pro Ser Leu
50 55 60
Lys Ser Arg Val Thr Ile Ser Val Asp Lys Ser Lys Asn Gln Phe Ser
65 70 75 80
Leu Lys Leu Ile Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Glu Gly Ile Gly Trp Pro Ser Phe Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 463
<211> 119
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 463
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gly
1 5 10 15
Thr Leu Ser Leu Thr Cys Ala Val Ser Gly Gly Ser Ile Ser Ser Ser
20 25 30
Asn Trp Trp Ser Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp
35 40 45
Ile Gly Glu Ile Tyr His Tyr Gly Asn Thr Asn Tyr Asn Pro Ser Leu
50 55 60
Lys Ser Arg Val Thr Ile Ser Val Asp Lys Ser Lys Asn Gln Phe Ser
65 70 75 80
Leu Lys Leu Ile Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Glu Gly Ile Gly Trp Pro Ser Phe Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 464
<211> 119
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 464
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gly
1 5 10 15
Thr Leu Ser Leu Thr Cys Ala Val Ser Gly Gly Ser Ile Ser Ser Ser
20 25 30
Asn Trp Trp Ser Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp
35 40 45
Ile Gly Glu Ile Tyr His Trp Gly Asn Thr Asn Tyr Asn Pro Ser Leu
50 55 60
Lys Ser Arg Val Thr Ile Ser Val Asp Lys Ser Lys Asn Gln Phe Ser
65 70 75 80
Leu Lys Leu Ile Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Glu Gly Ile Gly Trp Pro Ser Phe Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 465
<211> 119
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 465
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gly
1 5 10 15
Thr Leu Ser Leu Thr Cys Ala Val Ser Gly Gly Ser Ile Ser Ser Ser
20 25 30
Asn Trp Trp Ser Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp
35 40 45
Ile Gly Glu Ile Tyr His Ser Gly Trp Thr Asn Tyr Asn Pro Ser Leu
50 55 60
Lys Ser Arg Val Thr Ile Ser Val Asp Lys Ser Lys Asn Gln Phe Ser
65 70 75 80
Leu Lys Leu Ile Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Glu Gly Ile Gly Trp Pro Ser Phe Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 466
<211> 119
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 466
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gly
1 5 10 15
Thr Leu Ser Leu Thr Cys Ala Val Ser Gly Gly Ser Ile Ser Ser Ser
20 25 30
Asn Trp Trp Ser Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp
35 40 45
Ile Gly Glu Ile Tyr His Phe Gly Phe Thr Asn Tyr Asn Pro Ser Leu
50 55 60
Lys Ser Arg Val Thr Ile Ser Val Asp Lys Ser Lys Asn Gln Phe Ser
65 70 75 80
Leu Lys Leu Ile Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Glu Gly Ile Gly Trp Pro Ser Phe Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 467
<211> 119
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 467
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gly
1 5 10 15
Thr Leu Ser Leu Thr Cys Ala Val Ser Gly Gly Ser Ile Ser Ser Ser
20 25 30
Asn Trp Trp Ser Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp
35 40 45
Ile Gly Glu Ile Tyr His Tyr Gly Phe Thr Asn Tyr Asn Pro Ser Leu
50 55 60
Lys Ser Arg Val Thr Ile Ser Val Asp Lys Ser Lys Asn Gln Phe Ser
65 70 75 80
Leu Lys Leu Ile Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Glu Gly Ile Gly Trp Pro Ser Phe Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 468
<211> 119
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 468
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gly
1 5 10 15
Thr Leu Ser Leu Thr Cys Ala Val Ser Gly Gly Ser Ile Ser Ser Ser
20 25 30
Asn Trp Trp Ser Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp
35 40 45
Ile Gly Glu Ile Tyr His Trp Gly Phe Thr Asn Tyr Asn Pro Ser Leu
50 55 60
Lys Ser Arg Val Thr Ile Ser Val Asp Lys Ser Lys Asn Gln Phe Ser
65 70 75 80
Leu Lys Leu Ile Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Glu Gly Ile Gly Trp Pro Ser Phe Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 469
<211> 119
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 469
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gly
1 5 10 15
Thr Leu Ser Leu Thr Cys Ala Val Ser Gly Gly Ser Ile Ser Ser Ser
20 25 30
Asn Trp Trp Ser Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp
35 40 45
Ile Gly Glu Ile Tyr His Phe Gly Tyr Thr Asn Tyr Asn Pro Ser Leu
50 55 60
Lys Ser Arg Val Thr Ile Ser Val Asp Lys Ser Lys Asn Gln Phe Ser
65 70 75 80
Leu Lys Leu Ile Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Glu Gly Ile Gly Trp Pro Ser Phe Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 470
<211> 119
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 470
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gly
1 5 10 15
Thr Leu Ser Leu Thr Cys Ala Val Ser Gly Gly Ser Ile Ser Ser Ser
20 25 30
Asn Trp Trp Ser Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp
35 40 45
Ile Gly Glu Ile Tyr His Tyr Gly Tyr Thr Asn Tyr Asn Pro Ser Leu
50 55 60
Lys Ser Arg Val Thr Ile Ser Val Asp Lys Ser Lys Asn Gln Phe Ser
65 70 75 80
Leu Lys Leu Ile Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Glu Gly Ile Gly Trp Pro Ser Phe Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 471
<211> 119
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 471
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gly
1 5 10 15
Thr Leu Ser Leu Thr Cys Ala Val Ser Gly Gly Ser Ile Ser Ser Ser
20 25 30
Asn Trp Trp Ser Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp
35 40 45
Ile Gly Glu Ile Tyr His Trp Gly Tyr Thr Asn Tyr Asn Pro Ser Leu
50 55 60
Lys Ser Arg Val Thr Ile Ser Val Asp Lys Ser Lys Asn Gln Phe Ser
65 70 75 80
Leu Lys Leu Ile Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Glu Gly Ile Gly Trp Pro Ser Phe Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 472
<211> 119
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 472
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gly
1 5 10 15
Thr Leu Ser Leu Thr Cys Ala Val Ser Gly Gly Ser Ile Ser Ser Ser
20 25 30
Asn Trp Trp Ser Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp
35 40 45
Ile Gly Glu Ile Tyr His Phe Gly Trp Thr Asn Tyr Asn Pro Ser Leu
50 55 60
Lys Ser Arg Val Thr Ile Ser Val Asp Lys Ser Lys Asn Gln Phe Ser
65 70 75 80
Leu Lys Leu Ile Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Glu Gly Ile Gly Trp Pro Ser Phe Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 473
<211> 119
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 473
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gly
1 5 10 15
Thr Leu Ser Leu Thr Cys Ala Val Ser Gly Gly Ser Ile Ser Ser Ser
20 25 30
Asn Trp Trp Ser Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp
35 40 45
Ile Gly Glu Ile Tyr His Tyr Gly Trp Thr Asn Tyr Asn Pro Ser Leu
50 55 60
Lys Ser Arg Val Thr Ile Ser Val Asp Lys Ser Lys Asn Gln Phe Ser
65 70 75 80
Leu Lys Leu Ile Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Glu Gly Ile Gly Trp Pro Ser Phe Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 474
<211> 119
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 474
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gly
1 5 10 15
Thr Leu Ser Leu Thr Cys Ala Val Ser Gly Gly Ser Ile Ser Ser Ser
20 25 30
Asn Trp Trp Ser Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp
35 40 45
Ile Gly Glu Ile Tyr His Trp Gly Trp Thr Asn Tyr Asn Pro Ser Leu
50 55 60
Lys Ser Arg Val Thr Ile Ser Val Asp Lys Ser Lys Asn Gln Phe Ser
65 70 75 80
Leu Lys Leu Ile Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Glu Gly Ile Gly Trp Pro Ser Phe Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 475
<211> 119
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 475
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gly
1 5 10 15
Thr Leu Ser Leu Thr Cys Ala Val Ser Gly Gly Ser Ile Ser Ser Ser
20 25 30
Asn Trp Trp Ala Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp
35 40 45
Ile Gly Glu Ile Tyr His Ser Gly Asn Thr Asn Tyr Asn Pro Ser Leu
50 55 60
Lys Ser Arg Val Thr Ile Ser Val Asp Lys Ser Lys Asn Gln Phe Ser
65 70 75 80
Leu Lys Leu Ile Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Glu Gly Ile Gly Trp Pro Ser Phe Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 476
<211> 119
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 476
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gly
1 5 10 15
Thr Leu Ser Leu Thr Cys Ala Val Ser Gly Gly Ser Ile Ser Ser Ser
20 25 30
Asn Trp Leu Ser Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp
35 40 45
Ile Gly Glu Ile Tyr His Ser Gly Asn Thr Asn Tyr Asn Pro Ser Leu
50 55 60
Lys Ser Arg Val Thr Ile Ser Val Asp Lys Ser Lys Asn Gln Phe Ser
65 70 75 80
Leu Lys Leu Ile Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Glu Gly Ile Gly Trp Pro Ser Phe Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 477
<211> 119
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 477
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gly
1 5 10 15
Thr Leu Ser Leu Thr Cys Ala Val Ser Gly Gly Ser Ile Ser Ser Ser
20 25 30
Asn Trp Trp Ser Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp
35 40 45
Ile Gly Glu Ile Trp His Ser Gly Asn Thr Asn Tyr Asn Pro Ser Leu
50 55 60
Lys Ser Arg Val Thr Ile Ser Val Asp Lys Ser Lys Asn Gln Phe Ser
65 70 75 80
Leu Lys Leu Ile Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Glu Gly Ile Gly Trp Pro Ser Phe Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 478
<211> 119
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 478
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gly
1 5 10 15
Thr Leu Ser Leu Thr Cys Ala Val Ser Gly Gly Ser Ile Ser Ser Ser
20 25 30
Asn Trp Trp Ser Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp
35 40 45
Ile Gly Glu Ile Tyr His Ser Gly His Thr Asn Tyr Asn Pro Ser Leu
50 55 60
Lys Ser Arg Val Thr Ile Ser Val Asp Lys Ser Lys Asn Gln Phe Ser
65 70 75 80
Leu Lys Leu Ile Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Glu Gly Ile Gly Trp Pro Ser Phe Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 479
<211> 119
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 479
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gly
1 5 10 15
Thr Leu Ser Leu Thr Cys Ala Val Ser Gly Gly Ser Ile Ser Ser Ser
20 25 30
Asn Trp Trp Ser Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp
35 40 45
Ile Gly Glu Ile Tyr His Ser Gly Leu Thr Asn Tyr Asn Pro Ser Leu
50 55 60
Lys Ser Arg Val Thr Ile Ser Val Asp Lys Ser Lys Asn Gln Phe Ser
65 70 75 80
Leu Lys Leu Ile Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Glu Gly Ile Gly Trp Pro Ser Phe Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 480
<211> 119
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 480
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gly
1 5 10 15
Thr Leu Ser Leu Thr Cys Ala Val Ser Gly Gly Ser Ile Ser Ser Ser
20 25 30
Asn Trp Trp Ser Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp
35 40 45
Ile Gly Glu Ile Tyr His Ser Gly Asn Asp Asn Tyr Asn Pro Ser Leu
50 55 60
Lys Ser Arg Val Thr Ile Ser Val Asp Lys Ser Lys Asn Gln Phe Ser
65 70 75 80
Leu Lys Leu Ile Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Glu Gly Ile Gly Trp Pro Ser Phe Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 481
<211> 119
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 481
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gly
1 5 10 15
Thr Leu Ser Leu Thr Cys Ala Val Ser Gly Gly Ser Ile Ser Ser Ser
20 25 30
Asn Trp Trp Ser Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp
35 40 45
Ile Gly Glu Ile Tyr His Ser Gly Asn Thr Gln Tyr Asn Pro Ser Leu
50 55 60
Lys Ser Arg Val Thr Ile Ser Val Asp Lys Ser Lys Asn Gln Phe Ser
65 70 75 80
Leu Lys Leu Ile Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Glu Gly Ile Gly Trp Pro Ser Phe Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 482
<211> 119
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 482
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gly
1 5 10 15
Thr Leu Ser Leu Thr Cys Ala Val Ser Gly Gly Ser Ile Ser Ser Ser
20 25 30
Asn Trp Trp Ser Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp
35 40 45
Ile Gly Glu Ile Tyr His Ser Gly Asn Thr Asn Tyr Tyr Pro Ser Leu
50 55 60
Lys Ser Arg Val Thr Ile Ser Val Asp Lys Ser Lys Asn Gln Phe Ser
65 70 75 80
Leu Lys Leu Ile Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Glu Gly Ile Gly Trp Pro Ser Phe Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 483
<211> 119
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 483
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gly
1 5 10 15
Thr Leu Ser Leu Thr Cys Ala Val Ser Gly Gly Ser Ile Ser Ser Ser
20 25 30
Asn Trp Trp Ser Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp
35 40 45
Ile Gly Glu Ile Tyr His Ser Gly Asn Thr Asn Tyr Asn Pro Ser Leu
50 55 60
Lys Ser Arg Val Thr Ile Ser Val Asp Lys Ser Lys Asn Gln Phe Ser
65 70 75 80
Leu Lys Leu Ile Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Glu Gly Ile Gly Trp Pro Ser Phe Asp Ser Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 484
<211> 119
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 484
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gly
1 5 10 15
Thr Leu Ser Leu Thr Cys Ala Val Ser Gly Gly Ser Ile Ser Ser Ser
20 25 30
Asn Trp Trp Ser Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp
35 40 45
Ile Gly Glu Ile Tyr His Ser Gly Asn Thr Asn Tyr Asn Pro Ser Leu
50 55 60
Lys Ser Arg Val Thr Ile Ser Val Asp Lys Ser Lys Asn Gln Phe Ser
65 70 75 80
Leu Lys Leu Ile Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Glu Gly Ile Gly Trp Pro Ser Phe Asp Leu Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 485
<211> 119
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 485
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gly
1 5 10 15
Thr Leu Ser Leu Thr Cys Ala Val Ser Gly Gly Ser Ile Ser Ser Ser
20 25 30
Asn Trp Trp Ser Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp
35 40 45
Ile Gly Glu Ile Tyr His Ser Gly Asn Thr Asn Tyr Asn Pro Ser Leu
50 55 60
Lys Ser Arg Val Thr Ile Ser Val Asp Lys Ser Lys Asn Gln Phe Ser
65 70 75 80
Leu Lys Leu Ile Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Glu Gly Ile Gly Trp Pro Ser Phe Asp Ala Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 486
<211> 119
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 486
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gly
1 5 10 15
Thr Leu Ser Leu Thr Cys Ala Val Ser Gly Gly Ser Ile Ser Ser Ser
20 25 30
Asn Trp Trp Ser Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp
35 40 45
Ile Gly Glu Ile Tyr His Ser Gly Asn Thr Asn Tyr Asn Pro Ser Leu
50 55 60
Lys Ser Arg Val Thr Ile Ser Val Asp Lys Ser Lys Asn Gln Phe Ser
65 70 75 80
Leu Lys Leu Ile Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Glu Gly Ile Gly Trp Pro Ser Phe Asp His Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 487
<211> 119
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 487
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gly
1 5 10 15
Thr Leu Ser Leu Thr Cys Ala Val Ser Gly Gly Ser Ile Ser Ser Ser
20 25 30
Asn Trp Trp Ser Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp
35 40 45
Ile Gly Glu Ile Tyr His Trp Gly Trp Thr Asn Tyr Tyr Pro Ser Leu
50 55 60
Lys Ser Arg Val Thr Ile Ser Val Asp Lys Ser Lys Asn Gln Phe Ser
65 70 75 80
Leu Lys Leu Ile Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Glu Gly Ile Gly Trp Pro Ser Phe Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 488
<211> 119
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 488
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gly
1 5 10 15
Thr Leu Ser Leu Thr Cys Ala Val Ser Gly Gly Ser Ile Ser Ser Ser
20 25 30
Asn Trp Trp Ser Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp
35 40 45
Ile Gly Glu Ile Tyr His Ser Gly Asn Thr Asn Tyr Asn Pro Ser Leu
50 55 60
Lys Ser Arg Val Thr Ile Ser Val Asp Lys Ser Lys Asn Gln Phe Ser
65 70 75 80
Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Glu Gly Ile Gly Trp Pro Ser Phe Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 489
<211> 119
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 489
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gly
1 5 10 15
Thr Leu Ser Leu Thr Cys Ala Val Ser Gly Gly Ser Ile Ser Ser Ser
20 25 30
Asn Trp Trp Ser Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp
35 40 45
Ile Gly Glu Ile Tyr His Tyr Gly Trp Thr Asn Tyr Asn Pro Ser Leu
50 55 60
Lys Ser Arg Val Thr Ile Ser Val Asp Lys Ser Lys Asn Gln Phe Ser
65 70 75 80
Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Glu Gly Ile Gly Trp Pro Ser Phe Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 490
<211> 119
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 490
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gly
1 5 10 15
Thr Leu Ser Leu Thr Cys Ala Val Ser Gly Gly Ser Ile Ser Ser Ser
20 25 30
Asn Trp Trp Ser Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp
35 40 45
Ile Gly Glu Ile Tyr His Tyr Gly Tyr Thr Asn Tyr Asn Pro Ser Leu
50 55 60
Lys Ser Arg Val Thr Ile Ser Val Asp Lys Ser Lys Asn Gln Phe Ser
65 70 75 80
Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Glu Gly Ile Gly Trp Pro Ser Phe Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 491
<211> 108
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 491
Ser Ser Glu Leu Thr Gln Asp Pro Ala Ala Ser Val Ala Leu Gly Gln
1 5 10 15
Thr Val Arg Ile Thr Cys Gln Gly Asp Thr Leu Arg Asn Tyr Tyr Ala
20 25 30
Ser Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Ile Leu Val Ile Tyr
35 40 45
Gly Lys Asn Asn Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser Gly Ser
50 55 60
Ser Ser Gly Asn Thr Ala Ser Leu Thr Ile Thr Gly Ala Gln Ala Glu
65 70 75 80
Asp Glu Ala Asp Tyr Tyr Cys Asn Ser Arg Asp Ser Ser Gly Lys Asn
85 90 95
Leu Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
100 105
<210> 492
<211> 108
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 492
Ser Ser Glu Leu Thr Gln Asp Pro Ala Ala Ser Val Ala Leu Gly Gln
1 5 10 15
Thr Val Arg Ile Thr Cys Gln Gly Asp Thr Leu Arg Asn Tyr Tyr Ala
20 25 30
Ser Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Ile Leu Val Ile Tyr
35 40 45
Gly Lys Asn Asn Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser Gly Ser
50 55 60
Ser Ser Gly Asn Thr Ala Ser Leu Thr Ile Thr Gly Ala Gln Ala Glu
65 70 75 80
Asp Glu Ala Asp Tyr Tyr Cys Asn Ser Arg Ser Ser Ser Gly Lys Asn
85 90 95
Leu Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
100 105
<210> 493
<211> 108
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 493
Ser Ser Glu Leu Thr Gln Asp Pro Ala Ala Ser Val Ala Leu Gly Gln
1 5 10 15
Thr Val Arg Ile Thr Cys Gln Gly Asp Thr Leu Arg Asn Tyr Tyr Ala
20 25 30
Ser Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Ile Leu Val Ile Tyr
35 40 45
Ser Lys Asn Asn Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser Gly Ser
50 55 60
Ser Ser Gly Asn Thr Ala Ser Leu Thr Ile Thr Gly Ala Gln Ala Glu
65 70 75 80
Asp Glu Ala Asp Tyr Tyr Cys Asn Ser Arg Asp Ser Ser Gly Lys Asn
85 90 95
Leu Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
100 105
<210> 494
<211> 108
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 494
Ser Ser Glu Leu Thr Gln Asp Pro Ala Ala Ser Val Ala Leu Gly Gln
1 5 10 15
Thr Val Arg Ile Thr Cys Gln Gly Asp Thr Leu Arg Asn Tyr Tyr Ala
20 25 30
Ser Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Ile Leu Val Ile Tyr
35 40 45
Gly Ala Asn Asn Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser Gly Ser
50 55 60
Ser Ser Gly Asn Thr Ala Ser Leu Thr Ile Thr Gly Ala Gln Ala Glu
65 70 75 80
Asp Glu Ala Asp Tyr Tyr Cys Asn Ser Arg Asp Ser Ser Gly Lys Asn
85 90 95
Leu Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
100 105
<210> 495
<211> 108
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 495
Ser Ser Glu Leu Thr Gln Asp Pro Ala Ala Ser Val Ala Leu Gly Gln
1 5 10 15
Thr Val Arg Ile Thr Cys Gln Gly Asp Thr Leu Arg Asn Tyr Tyr Ala
20 25 30
Ser Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Ile Leu Val Ile Tyr
35 40 45
Gly His Asn Asn Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser Gly Ser
50 55 60
Ser Ser Gly Asn Thr Ala Ser Leu Thr Ile Thr Gly Ala Gln Ala Glu
65 70 75 80
Asp Glu Ala Asp Tyr Tyr Cys Asn Ser Arg Asp Ser Ser Gly Lys Asn
85 90 95
Leu Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
100 105
<210> 496
<211> 108
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 496
Ser Ser Glu Leu Thr Gln Asp Pro Ala Ala Ser Val Ala Leu Gly Gln
1 5 10 15
Thr Val Arg Ile Thr Cys Gln Gly Asp Thr Leu Arg Asn Tyr Tyr Ala
20 25 30
Ser Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Ile Leu Val Ile Tyr
35 40 45
Gly Leu Asn Asn Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser Gly Ser
50 55 60
Ser Ser Gly Asn Thr Ala Ser Leu Thr Ile Thr Gly Ala Gln Ala Glu
65 70 75 80
Asp Glu Ala Asp Tyr Tyr Cys Asn Ser Arg Asp Ser Ser Gly Lys Asn
85 90 95
Leu Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
100 105
<210> 497
<211> 108
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 497
Ser Ser Glu Leu Thr Gln Asp Pro Ala Ala Ser Val Ala Leu Gly Gln
1 5 10 15
Thr Val Arg Ile Thr Cys Gln Gly Asp Thr Leu Arg Asn Tyr Tyr Ala
20 25 30
Ser Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Ile Leu Val Ile Tyr
35 40 45
Gly Lys Asn Asn Leu Pro Ser Gly Ile Pro Asp Arg Phe Ser Gly Ser
50 55 60
Ser Ser Gly Asn Thr Ala Ser Leu Thr Ile Thr Gly Ala Gln Ala Glu
65 70 75 80
Asp Glu Ala Asp Tyr Tyr Cys Asn Ser Arg Asp Ser Ser Gly Lys Asn
85 90 95
Leu Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
100 105
<210> 498
<211> 108
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 498
Ser Ser Glu Leu Thr Gln Asp Pro Ala Ala Ser Val Ala Leu Gly Gln
1 5 10 15
Thr Val Arg Ile Thr Cys Gln Gly Asp Thr Leu Arg Asn Tyr Tyr Ala
20 25 30
Ser Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Ile Leu Val Ile Tyr
35 40 45
Gly Lys Asn Asn Gln Pro Ser Gly Ile Pro Asp Arg Phe Ser Gly Ser
50 55 60
Ser Ser Gly Asn Thr Ala Ser Leu Thr Ile Thr Gly Ala Gln Ala Glu
65 70 75 80
Asp Glu Ala Asp Tyr Tyr Cys Asn Ser Arg Asp Ser Ser Gly Lys Asn
85 90 95
Leu Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
100 105
<210> 499
<211> 108
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 499
Ser Ser Glu Leu Thr Gln Asp Pro Ala Ala Ser Val Ala Leu Gly Gln
1 5 10 15
Thr Val Arg Ile Thr Cys Gln Gly Asp Thr Leu Arg Asn Tyr Tyr Ala
20 25 30
Ser Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Ile Leu Val Ile Tyr
35 40 45
Gly Lys Asn Asn Tyr Pro Ser Gly Ile Pro Asp Arg Phe Ser Gly Ser
50 55 60
Ser Ser Gly Asn Thr Ala Ser Leu Thr Ile Thr Gly Ala Gln Ala Glu
65 70 75 80
Asp Glu Ala Asp Tyr Tyr Cys Asn Ser Arg Asp Ser Ser Gly Lys Asn
85 90 95
Leu Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
100 105
<210> 500
<211> 108
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 500
Ser Ser Glu Leu Thr Gln Asp Pro Ala Ala Ser Val Ala Leu Gly Gln
1 5 10 15
Thr Val Arg Ile Thr Cys Gln Gly Asp Thr Leu Arg Asn Tyr Tyr Ala
20 25 30
Ser Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Ile Leu Val Ile Tyr
35 40 45
Gly His Asn Asn Leu Pro Ser Gly Ile Pro Asp Arg Phe Ser Gly Ser
50 55 60
Ser Ser Gly Asn Thr Ala Ser Leu Thr Ile Thr Gly Ala Gln Ala Glu
65 70 75 80
Asp Glu Ala Asp Tyr Tyr Cys Asn Ser Arg Asp Ser Ser Gly Lys Asn
85 90 95
Leu Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
100 105
<210> 501
<211> 108
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 501
Ser Ser Glu Leu Thr Gln Asp Pro Ala Ala Ser Val Ala Leu Gly Gln
1 5 10 15
Thr Val Arg Ile Thr Cys Gln Gly Asp Thr Leu Arg Asn Tyr Tyr Ala
20 25 30
Ser Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Ile Leu Val Ile Tyr
35 40 45
Gly His Asn Asn Tyr Pro Ser Gly Ile Pro Asp Arg Phe Ser Gly Ser
50 55 60
Ser Ser Gly Asn Thr Ala Ser Leu Thr Ile Thr Gly Ala Gln Ala Glu
65 70 75 80
Asp Glu Ala Asp Tyr Tyr Cys Asn Ser Arg Asp Ser Ser Gly Lys Asn
85 90 95
Leu Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
100 105
<210> 502
<211> 108
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 502
Ser Ser Glu Leu Thr Gln Asp Pro Ala Ala Ser Val Ala Leu Gly Gln
1 5 10 15
Thr Val Arg Ile Thr Cys Gln Gly Asp Thr Leu Arg Ser Tyr Tyr Ala
20 25 30
Ser Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Ile Leu Val Ile Tyr
35 40 45
Gly Lys Asn Asn Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser Gly Ser
50 55 60
Ser Ser Gly Asn Thr Ala Ser Leu Thr Ile Thr Gly Ala Gln Ala Glu
65 70 75 80
Asp Glu Ala Asp Tyr Tyr Cys Asn Ser Arg Asp Ser Ser Gly Lys Asn
85 90 95
Leu Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
100 105
<210> 503
<211> 108
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 503
Ser Ser Glu Leu Thr Gln Asp Pro Ala Ala Ser Val Ala Leu Gly Gln
1 5 10 15
Thr Val Arg Ile Thr Cys Gln Gly Asp Thr Leu Arg Asn Tyr Tyr Ala
20 25 30
Ser Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Ile Leu Val Ile Tyr
35 40 45
Gly Lys Asn Asn Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser Gly Ser
50 55 60
Ser Ser Gly Asn Thr Ala Ser Leu Thr Ile Thr Gly Ala Gln Ala Glu
65 70 75 80
Asp Glu Ala Asp Tyr Tyr Cys Asn Ser Arg Glu Ser Ser Gly Lys Asn
85 90 95
Leu Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
100 105
<210> 504
<211> 108
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 504
Ser Ser Glu Leu Thr Gln Asp Pro Ala Ala Ser Val Ala Leu Gly Gln
1 5 10 15
Thr Val Arg Ile Thr Cys Gln Gly Asp Thr Leu Arg Asn Tyr Tyr Ala
20 25 30
Ser Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Ile Leu Val Ile Tyr
35 40 45
Gly Lys Asn Asn Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser Gly Ser
50 55 60
Ser Ser Gly Asn Thr Ala Ser Leu Thr Ile Thr Gly Ala Gln Ala Glu
65 70 75 80
Asp Glu Ala Asp Tyr Tyr Cys Asn Ser Arg Asp Leu Ser Gly Lys Asn
85 90 95
Leu Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
100 105
<210> 505
<211> 108
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 505
Ser Ser Glu Leu Thr Gln Asp Pro Ala Ala Ser Val Ala Leu Gly Gln
1 5 10 15
Thr Val Arg Ile Thr Cys Gln Gly Asp Thr Leu Arg Asn Tyr Tyr Ala
20 25 30
Ser Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Ile Leu Val Ile Tyr
35 40 45
Gly Lys Asn Asn Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser Gly Ser
50 55 60
Ser Ser Gly Asn Thr Ala Ser Leu Thr Ile Thr Gly Ala Gln Ala Glu
65 70 75 80
Asp Glu Ala Asp Tyr Tyr Cys Asn Ser Arg Asp Glu Ser Gly Lys Asn
85 90 95
Leu Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
100 105
<210> 506
<211> 108
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 506
Ser Ser Glu Leu Thr Gln Asp Pro Ala Ala Ser Val Ala Leu Gly Gln
1 5 10 15
Thr Val Arg Ile Thr Cys Gln Gly Asp Thr Leu Arg Asn Tyr Tyr Ala
20 25 30
Ser Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Ile Leu Val Ile Tyr
35 40 45
Gly Lys Asn Asn Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser Gly Ser
50 55 60
Ser Ser Gly Asn Thr Ala Ser Leu Thr Ile Thr Gly Ala Gln Ala Glu
65 70 75 80
Asp Glu Ala Asp Tyr Tyr Cys Asn Ser Arg Asp Phe Ser Gly Lys Asn
85 90 95
Leu Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
100 105
<210> 507
<211> 108
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 507
Ser Ser Glu Leu Thr Gln Asp Pro Ala Ala Ser Val Ala Leu Gly Gln
1 5 10 15
Thr Val Arg Ile Thr Cys Gln Gly Asp Thr Leu Arg Ser Tyr Tyr Ala
20 25 30
Ser Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Ile Leu Val Ile Tyr
35 40 45
Gly Lys Asn Asn Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser Gly Ser
50 55 60
Ser Ser Gly Asn Thr Ala Ser Leu Thr Ile Thr Gly Ala Gln Ala Glu
65 70 75 80
Asp Glu Ala Asp Tyr Tyr Cys Asn Ser Arg Glu Ser Ser Gly Lys Asn
85 90 95
Leu Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
100 105
<210> 508
<211> 108
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 508
Ser Ser Glu Leu Thr Gln Asp Pro Ala Ala Ser Val Ala Leu Gly Gln
1 5 10 15
Thr Val Arg Ile Thr Cys Gln Gly Asp Thr Leu Arg Ser Tyr Tyr Ala
20 25 30
Ser Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Ile Leu Val Ile Tyr
35 40 45
Gly Lys Asn Asn Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser Gly Ser
50 55 60
Ser Ser Gly Asn Thr Ala Ser Leu Thr Ile Thr Gly Ala Gln Ala Glu
65 70 75 80
Asp Glu Ala Asp Tyr Tyr Cys Asn Ser Arg Asp Leu Ser Gly Lys Asn
85 90 95
Leu Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
100 105
<210> 509
<211> 108
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 509
Ser Ser Glu Leu Thr Gln Asp Pro Ala Ala Ser Val Ala Leu Gly Gln
1 5 10 15
Thr Val Arg Ile Thr Cys Gln Gly Asp Thr Leu Arg Ser Tyr Tyr Ala
20 25 30
Ser Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Ile Leu Val Ile Tyr
35 40 45
Gly Lys Asn Asn Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser Gly Ser
50 55 60
Ser Ser Gly Asn Thr Ala Ser Leu Thr Ile Thr Gly Ala Gln Ala Glu
65 70 75 80
Asp Glu Ala Asp Tyr Tyr Cys Asn Ser Arg Asp Glu Ser Gly Lys Asn
85 90 95
Leu Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
100 105
<210> 510
<211> 108
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 510
Ser Ser Glu Leu Thr Gln Asp Pro Ala Ala Ser Val Ala Leu Gly Gln
1 5 10 15
Thr Val Arg Ile Thr Cys Gln Gly Asp Thr Leu Arg Ser Tyr Tyr Ala
20 25 30
Ser Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Ile Leu Val Ile Tyr
35 40 45
Gly Lys Asn Asn Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser Gly Ser
50 55 60
Ser Ser Gly Asn Thr Ala Ser Leu Thr Ile Thr Gly Ala Gln Ala Glu
65 70 75 80
Asp Glu Ala Asp Tyr Tyr Cys Asn Ser Arg Asp Phe Ser Gly Lys Asn
85 90 95
Leu Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
100 105
<210> 511
<211> 114
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 511
Asn Trp Val Asn Val Ile Ser Asp Leu Lys Lys Ile Glu Asp Leu Ile
1 5 10 15
Gln Ser Met His Ile Asp Ala Thr Leu Tyr Thr Glu Ser Asp Val His
20 25 30
Pro Ser Cys Lys Val Thr Ala Met Lys Cys Phe Leu Leu Glu Leu Gln
35 40 45
Val Ile Ser Leu Glu Ser Gly Asp Ala Ser Ile His Asp Thr Val Glu
50 55 60
Asn Leu Ile Ile Leu Ala Asn Asn Ser Leu Ser Ser Asn Gly Asn Val
65 70 75 80
Thr Glu Ser Gly Cys Lys Glu Cys Glu Glu Leu Glu Glu Lys Asn Ile
85 90 95
Lys Glu Phe Leu Gln Ser Phe Val His Ile Val Gln Met Phe Ile Asn
100 105 110
Thr Ser
<210> 512
<211> 211
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 512
Ile Thr Cys Pro Pro Pro Met Ser Val Glu His Ala Asp Ile Trp Val
1 5 10 15
Lys Ser Tyr Ser Leu Tyr Ser Arg Glu Arg Tyr Ile Cys Asn Ser Gly
20 25 30
Phe Lys Arg Lys Ala Gly Thr Ser Ser Leu Thr Glu Cys Val Leu Asn
35 40 45
Lys Ala Thr Asn Val Ala His Trp Thr Thr Pro Ser Leu Lys Cys Ile
50 55 60
Arg Asp Pro Ala Leu Val His Gln Arg Pro Ala Pro Pro Ser Thr Val
65 70 75 80
Thr Thr Ala Gly Val Thr Pro Gln Pro Glu Ser Leu Ser Pro Ser Gly
85 90 95
Lys Glu Pro Ala Ala Ser Ser Pro Ser Ser Asn Asn Thr Ala Ala Thr
100 105 110
Thr Ala Ala Ile Val Pro Gly Ser Gln Leu Met Pro Ser Lys Ser Pro
115 120 125
Ser Thr Gly Thr Thr Glu Ile Ser Ser His Glu Ser Ser His Gly Thr
130 135 140
Pro Ser Gln Thr Thr Ala Lys Asn Trp Glu Leu Thr Ala Ser Ala Ser
145 150 155 160
His Gln Pro Pro Gly Val Tyr Pro Gln Gly His Ser Asp Thr Thr Lys
165 170 175
Arg Val Gly Ser Ile Glu Gly Arg Gly Ser Gly Leu Asn Asp Ile Phe
180 185 190
Glu Ala Gln Lys Ile Glu Trp His Glu Gly Ser His His His His His
195 200 205
His His His
210
<210> 513
<211> 107
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 513
Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu
1 5 10 15
Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe
20 25 30
Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln
35 40 45
Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser
50 55 60
Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu
65 70 75 80
Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser
85 90 95
Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
100 105
<210> 514
<211> 106
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 514
Gly Gln Pro Lys Ala Ala Pro Ser Val Thr Leu Phe Pro Pro Ser Ser
1 5 10 15
Glu Glu Leu Gln Ala Asn Lys Ala Thr Leu Val Cys Leu Ile Ser Asp
20 25 30
Phe Tyr Pro Gly Ala Val Thr Val Ala Trp Lys Ala Asp Ser Ser Pro
35 40 45
Val Lys Ala Gly Val Glu Thr Thr Thr Pro Ser Lys Gln Ser Asn Asn
50 55 60
Lys Tyr Ala Ala Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys
65 70 75 80
Ser His Arg Ser Tyr Ser Cys Gln Val Thr His Glu Gly Ser Thr Val
85 90 95
Glu Lys Thr Val Ala Pro Thr Glu Cys Ser
100 105
<210> 515
<211> 448
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 515
Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu
1 5 10 15
Ser Leu Lys Ile Ser Cys Lys Val Ser Gly Tyr Phe Phe Thr Thr Tyr
20 25 30
Trp Ile Gly Trp Val Arg Gln Met Pro Gly Lys Gly Leu Glu Tyr Met
35 40 45
Gly Ile Ile Tyr Pro Gly Asp Ser Asp Thr Arg Tyr Ser Pro Ser Phe
50 55 60
Gln Gly Gln Val Thr Ile Ser Ala Asp Lys Ser Ile Ser Thr Ala Tyr
65 70 75 80
Leu Gln Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys
85 90 95
Ala Arg Gly Gly Asn Trp Asn Cys Phe Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro
115 120 125
Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly
130 135 140
Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn
145 150 155 160
Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln
165 170 175
Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser
180 185 190
Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser
195 200 205
Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr
210 215 220
His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser
225 230 235 240
Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg
245 250 255
Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro
260 265 270
Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
275 280 285
Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val
290 295 300
Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
305 310 315 320
Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr
325 330 335
Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu
340 345 350
Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys
355 360 365
Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser
370 375 380
Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp
385 390 395 400
Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser
405 410 415
Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala
420 425 430
Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
435 440 445
<210> 516
<211> 214
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 516
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser
20 25 30
Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu
35 40 45
Ile Tyr Gly Ala Ser Arg Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu
65 70 75 80
Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Arg Tyr Gly Ser Ser His
85 90 95
Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Ser Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys
210
<210> 517
<211> 357
<212> DNA
<213>homo sapiens (Homo sapiens)
<400> 517
caggtgcagc tgcaggaatc tggccccgga ctggtgaaac ctagcggcac cctgagcctg 60
acctgcgccg tgagcggcgg cagcatcagc agcagcaact ggtggagctg ggtccgccag 120
cctcctggca agggcctgga atggatcggc gagatctacc actacggcta caccaactac 180
aaccccagcc tgaagtcccg ggtgaccatc agcgtggaca agagcaagaa ccagttcagc 240
ctgaagctgt ccagcgtgac agccgccgac accgccgtgt actactgcgc cagagaggga 300
atcggctggc ccagcttcga ttactggggc cagggcaccc tggtgacagt gtcctca 357
<210> 518
<211> 327
<212> DNA
<213>homo sapiens (Homo sapiens)
<400> 518
agcagcgagc tgacccagga tcccgctgct tccgtggctc tgggccagac cgtgcggatc 60
acctgtcagg gcgacaccct gcggagctac tacgccagct ggtatcagca gaagcccggc 120
caggccccca tcctggtgat ctacggcaag aacaaccggc ccagcggcat ccccgacaga 180
ttcagcggca gcagcagcgg caacaccgcc agcctgacca tcactggcgc tcaggccgag 240
gacgaggccg actactactg caacagccgg gacctttccg gcaagaacct ggtgttcggc 300
ggaggcacca agctgaccgt cctaggt 327
<210> 519
<211> 11
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 519
Asn Ser Arg Asp Phe Ser Gly Lys Asn Leu Val
1 5 10
<210> 520
<211> 186
<212> PRT
<213>homo sapiens (Homo sapiens)
<400> 520
Ile Thr Cys Pro Pro Pro Met Ser Val Glu His Ala Asp Ile Trp Val
1 5 10 15
Lys Ser Tyr Ser Leu Tyr Ser Arg Glu Arg Tyr Ile Cys Asn Ser Gly
20 25 30
Phe Lys Arg Lys Ala Gly Thr Ser Ser Leu Thr Glu Cys Val Leu Asn
35 40 45
Lys Ala Thr Asn Val Ala His Trp Thr Thr Pro Ser Leu Lys Cys Ile
50 55 60
Arg Asp Pro Ala Leu Val His Gln Arg Pro Ala Pro Pro Ser Thr Val
65 70 75 80
Thr Thr Ala Gly Val Thr Pro Gln Pro Glu Ser Leu Ser Pro Ser Gly
85 90 95
Lys Glu Pro Ala Ala Ser Ser Pro Ser Ser Asn Asn Thr Ala Ala Thr
100 105 110
Thr Ala Ala Ile Val Pro Gly Ser Gln Leu Met Pro Ser Lys Ser Pro
115 120 125
Ser Thr Gly Thr Thr Glu Ile Ser Ser His Glu Ser Ser His Gly Thr
130 135 140
Pro Ser Gln Thr Thr Ala Lys Asn Trp Glu Leu Thr Ala Ser Ala Ser
145 150 155 160
His Gln Pro Pro Gly Val Tyr Pro Gln Gly His Ser Asp Thr Thr Lys
165 170 175
Arg Val Gly Ser Ile Glu Gly Arg Gly Ser
180 185

Claims (104)

1. a kind of antibody, it includes variable heavy chain and variable light, wherein the antibody specificity combine and include human IL-15 The epitope of Q108 residue, wherein the IL-15 and IL-15 receptor alpha (IL-15R α) is compound.
2. antibody as described in claim 1, wherein the antibody has affinity to the epitope comprising such as pass through surface What plasmon resonance was measured is less than 1.8x10-9The dissociation constant (KD) of M.
3. antibody according to claim 1 or 2, wherein the epitope also includes S7 the and N112 residue of human IL-15.
4. antibody according to any one of claim 1-3, wherein the dissociation constant (KD) is less than 1x10-9M。
5. a kind of antibody, it includes the HCDR1 of the amino acid sequence containing SEQ ID NO:16, the ammonia containing SEQ ID NO:17 HCDR3, the amino acid containing SEQ ID NO:25 of the HCDR2 of base acid sequence, amino acid sequence containing SEQ ID NO:20 The LCDR1 of sequence, the LCDR2 of amino acid sequence containing SEQ ID NO:28 and the amino acid sequence containing SEQ ID NO:29 LCDR3, wherein the antibody specificity combine human IL-15, wherein the IL-15 and IL-15 receptor alpha (IL-15R α) are multiple It closes.
6. antibody according to claim 5, wherein the antibody includes the amino acid sequence containing SEQ ID NO:18 HCDR2。
7. antibody according to claim 5 or 6, wherein the antibody includes the amino acid sequence containing SEQ ID NO:26 LCDR1 and the amino acid sequence containing SEQ ID NO:30 LCDR3.
8. antibody according to claim 7, wherein the antibody includes the amino acid sequence containing SEQ ID NO:18 The heavy chain FR3 of HCDR2 and the amino acid sequence containing SEQ ID NO:13.
9. antibody according to claim 7 or 8, wherein the antibody includes the amino acid sequence containing SEQ ID NO:4 Heavy chain variable region.
10. antibody according to claim 9, wherein the antibody includes the amino acid sequence containing SEQ ID NO:5 Light chain variable region.
11. antibody according to claim 9 or 10, wherein the antibody includes the amino acid sequence containing SEQ ID NO:6 The light chain of column.
12. antibody according to claim 7 or 8, wherein the antibody includes the amino acid sequence containing SEQ ID NO:5 Light chain variable region.
13. antibody according to claim 12, wherein the antibody includes the amino acid sequence containing SEQ ID NO:6 Light chain.
14. antibody according to claim 5 or 6, wherein the antibody includes the amino acid sequence containing SEQ ID NO:27 The LCDR3 of the LCDR1 of column and the amino acid sequence containing SEQ ID NO:31.
15. antibody according to claim 14, wherein the antibody includes the amino acid sequence containing SEQ ID NO:454 Heavy chain variable region and the amino acid sequence containing SEQ ID NO:8 light chain variable region.
16. the antibody according to any one of claim 5,6,14 and 15, wherein the antibody includes to contain SEQ ID The light chain of the amino acid sequence of NO:9.
17. antibody according to claim 5 or 6, wherein the heavy chain FR3 includes the amino acid sequence of SEQ ID NO:12 Column.
18. antibody according to claim 17, wherein the heavy chain FR3 includes the amino acid sequence of SEQ ID NO:13.
19. antibody according to claim 5 or 6, wherein the antibody includes the amino acid sequence containing SEQ ID NO:26 The LCDR3 of the LCDR1 of column and the amino acid sequence containing SEQ ID NO:31.
20. the antibody according to claim 5 or 19, wherein the antibody includes the amino acid sequence containing SEQ ID NO:4 The light chain variable region of the heavy chain variable region of column and the amino acid sequence containing SEQ ID NO:455.
21. antibody described in 9 or 20 according to claim 1, wherein the antibody includes the amino acid containing SEQ ID NO:456 The light chain of sequence.
22. antibody according to claim 5 or 6, wherein the antibody includes the amino acid sequence containing SEQ ID NO:27 The LCDR3 of the LCDR1 of column and the amino acid sequence containing SEQ ID NO:30.
23. antibody according to claim 22, wherein the antibody includes the amino acid sequence containing SEQ ID NO:4 The light chain variable region of heavy chain variable region and the amino acid sequence containing SEQ ID NO:457.
24. the antibody according to claim 22 or 23, wherein the antibody includes the amino acid containing SEQ ID NO:458 The light chain of sequence.
25. antibody according to claim 5 or 6, wherein the antibody includes the amino acid sequence containing SEQ ID NO:27 The LCDR3 of the LCDR1 of column and the amino acid sequence containing SEQ ID NO:519.
26. antibody according to claim 25, wherein the antibody includes the amino acid sequence containing SEQ ID NO:4 The light chain variable region of heavy chain variable region and the amino acid sequence containing SEQ ID NO:459.
27. antibody according to claim 26, wherein the antibody includes the amino acid sequence containing SEQ ID NO:460 Light chain.
28. the antibody according to claim 5 or 17, wherein the antibody includes the amino acid sequence containing SEQ ID NO:19 The HCDR2 of column, the LCDR1 of amino acid sequence containing SEQ ID NO:27, amino acid sequence containing SEQ ID NO:31 The heavy chain FR3 of LCDR3 and the amino acid sequence containing SEQ ID NO:14.
29. antibody according to claim 28, wherein the antibody includes the amino acid sequence containing SEQ ID NO:7 The light chain variable region of heavy chain variable region and the amino acid sequence containing SEQ ID NO:8.
30. antibody according to claim 29, wherein the antibody includes the amino acid sequence containing SEQ ID NO:9 Light chain.
31. a kind of antibody it includes the heavy chain variable region of the amino acid sequence containing SEQ ID NO:1 and contains SEQ ID NO: The light chain variable region of 2 amino acid sequence, wherein the antibody specificity combine human IL-15, wherein the IL-15 and IL- 15 receptor alphas (IL-15R α) are compound.
32. antibody according to claim 31, wherein the antibody includes
(a) heavy chain variable region of the amino acid sequence containing SEQ ID NO:4 and amino acid sequence containing SEQ ID NO:5 Light chain variable region；
(b) heavy chain variable region of the amino acid sequence containing SEQ ID NO:454 and amino acid sequence containing SEQ ID NO:8 Light chain variable region；
(c) heavy chain variable region of the amino acid sequence containing SEQ ID NO:4 and amino acid sequence containing SEQ ID NO:455 Light chain variable region；
(d) heavy chain variable region of the amino acid sequence containing SEQ ID NO:4 and amino acid sequence containing SEQ ID NO:457 Light chain variable region；Or
(e) heavy chain variable region of the amino acid sequence containing SEQ ID NO:4 and amino acid sequence containing SEQ ID NO:459 Light chain variable region.
33. a kind of antibody for specifically combining human IL-15, wherein the IL-15 and IL-15 receptor alpha (IL-15R α) is compound, Wherein the antibody includes
(a) heavy chain variable region of the amino acid sequence containing SEQ ID NO:4 and amino acid sequence containing SEQ ID NO:8 Light chain variable region；
(b) heavy chain variable region of the amino acid sequence containing SEQ ID NO:4 and amino acid sequence containing SEQ ID NO:503 Light chain variable region；
(c) heavy chain variable region of the amino acid sequence containing SEQ ID NO:4 and amino acid sequence containing SEQ ID NO:505 Light chain variable region；
(d) heavy chain variable region of the amino acid sequence containing SEQ ID NO:4 and amino acid sequence containing SEQ ID NO:507 Light chain variable region；
(e) heavy chain variable region of the amino acid sequence containing SEQ ID NO:4 and amino acid sequence containing SEQ ID NO:509 Light chain variable region；
(f) heavy chain variable region of the amino acid sequence containing SEQ ID NO:4 and amino acid sequence containing SEQ ID NO:510 Light chain variable region；
(g) heavy chain variable region of the amino acid sequence containing SEQ ID NO:454 and amino acid sequence containing SEQ ID NO:455 The light chain variable region of column；
(h) heavy chain variable region of the amino acid sequence containing SEQ ID NO:454 and amino acid sequence containing SEQ ID NO:503 The light chain variable region of column；
(i) heavy chain variable region of the amino acid sequence containing SEQ ID NO:454 and amino acid sequence containing SEQ ID NO:457 The light chain variable region of column；
(j) heavy chain variable region of the amino acid sequence containing SEQ ID NO:454 and amino acid sequence containing SEQ ID NO:505 The light chain variable region of column；
(k) heavy chain variable region of the amino acid sequence containing SEQ ID NO:454 and amino acid sequence containing SEQ ID NO:506 The light chain variable region of column；
(1) heavy chain variable region of the amino acid sequence containing SEQ ID NO:454 and amino acid sequence containing SEQ ID NO:507 The light chain variable region of column；
(m) heavy chain variable region of the amino acid sequence containing SEQ ID NO:454 and amino acid sequence containing SEQ ID NO:5 Light chain variable region；
(n) heavy chain variable region of the amino acid sequence containing SEQ ID NO:454 and amino acid sequence containing SEQ ID NO:509 The light chain variable region of column；Or
(o) heavy chain variable region of the amino acid sequence containing SEQ ID NO:454 and amino acid sequence containing SEQ ID NO:510 The light chain variable region of column.
34. according to claim 1 to antibody described in any one of 33, wherein the antibody includes IgG constant domain.
35. according to claim 1 to antibody described in any one of 34, wherein the antibody includes IgG4 constant domain.
36. antibody according to claim 35, wherein the IgG4 constant domain includes selected from the group being made up of Amino acid sequence: SEQ ID NO:49, SEQ ID NO:44, SEQ ID NO:45, SEQ ID NO:46, SEQ ID NO: 47, SEQ ID NO:48, SEQ ID NO:50 and SEQ ID NO:51.
37. according to claim 1 to antibody described in any one of 34, wherein the antibody includes IgG1 constant domain.
38. the antibody according to claim 37, wherein the IgG1 constant domain includes selected from the group being made up of Amino acid sequence: SEQ ID NO:32, SEQ ID NO:33, SEQ ID NO:34, SEQ ID NO:35, SEQ ID NO: 36, SEQ ID NO:37, SEQ ID NO:38 and SEQ ID NO:39.
39. according to claim 1 to antibody described in any one of 34, wherein the antibody includes IgG2 constant domain.
40. antibody according to claim 39, wherein the IgG2 constant domain includes selected from the group being made up of Amino acid sequence: SEQ ID NO:40, SEQ ID NO:41, SEQ ID NO:42 and SEQ ID NO:43.
41. according to claim 1 to antibody described in any one of 40, wherein the antibody is in natural kill (NK) cell Proliferation With about 0.1pM to the IC of about 900pM in measurement50Inhibit the proliferation of NK cell.
42. according to claim 1 to antibody described in any one of 41, wherein the antibody is in NK cell proliferating determining with about The IC of 1pM to about 60pM50Inhibit the proliferation of NK cell.
43. according to claim 1 to antibody described in any one of 42, wherein the antibody is in NK cell proliferating determining with about The IC of 5pM to about 35pM50Inhibit the proliferation of NK cell.
44. according to claim 1 to antibody described in any one of 43, wherein the antibody can neutralize IL-15.
45. according to claim 1 to antibody described in any one of 44, wherein the antibody can reduce circulation NK cell.
46. the antibody according to any one of claim 5 to 45, wherein the antibody combines the Q108 comprising human IL-15 The epitope of residue.
47. antibody according to claim 46, wherein the epitope also includes S7 the and N112 residue of human IL-15.
48. the antibody according to any one of claim 5 to 46, wherein the antibody on human IL-15 has affinity, It is less than about 1.8x10 including what is measured by such as surface plasmon resonance-9The dissociation constant (KD) of M, or the wherein solution It is less than 1x10 from constant (KD)-9M。
49. a kind of antibody of combination IL-15, wherein the IL-15 and IL-15 receptor alpha (IL-15R α) is compound, the antibody packet Containing heavy chain variable region and light chain variable region, wherein the heavy chain variable region includes the amino acid sequence of SEQ ID NO:4.
50. a kind of antibody of combination IL-15, wherein the IL-15 and IL-15 receptor alpha (IL-15R α) is compound, the antibody packet Containing heavy chain variable region and light chain variable region, wherein the light chain variable region includes the amino acid sequence of SEQ ID NO:5.
51. the antibody as described in claim 50 or 51, wherein the heavy chain variable region includes the amino acid sequence of SEQ ID NO:4 Column, and the light chain variable region includes the amino acid sequence of SEQ ID NO:5.
52. the antibody as described in any one of claim 49-51, wherein the antibody includes the ammonia containing SEQ ID NO:6 The light chain of base acid sequence.
53. the antibody as described in any one of claim 49-51 also includes the amino acid sequence containing SEQ ID NO:49 Heavy chain constant region.
54. the antibody as described in any one of claim 49-51 also includes the amino acid sequence containing SEQ ID NO:49 Heavy chain constant region, wherein the antibody include the amino acid sequence containing SEQ ID NO:6 light chain.
55. a kind of composition, it includes according to claim 1 to antibody described in any one of 54 and pharmaceutically acceptable load Agent or excipient.
56. a kind of method for the chylous diarrhea for treating subject in need, the method includes applying to combine to the subject The antibody of IL-15, wherein the IL-15 and IL-15 receptor alpha (IL-15R α) is compound.
57. a kind of method for the chylous diarrhea for treating subject in need, the method includes applying basis to the subject Antibody described in any one of claim 1 to 54.
58. it is a kind of for repairing the method for suffering from the mucous membrane of small intestine of subject of sensitive seitan, gluten or chylous diarrhea, it is described Method includes applying to the subject according to claim 1 to antibody described in any one of 54.
59. a kind of for increasing the average fluff height and crypts that suffer from the subject of sensitive seitan, gluten or chylous diarrhea The method of depth (V/C) ratio, the method includes applying to the subject according to claim 1 to described in any one of 54 Antibody.
60. it is a kind of for increasing the method for suffering from the small intestinal villous height of subject of sensitive seitan, gluten or chylous diarrhea, The method includes applying to the subject according to claim 1 to antibody described in any one of 54.
61. a kind of method for reducing the anti-gliadin antibody of subject in need, the method includes to described Subject applies according to claim 1 to antibody described in any one of 54.
62. a kind of method for repairing the intestinal mucosa injury of seitan induction, the method includes applying basis to subject Antibody described in any one of claim 1 to 54.
63. the method according to claim 61 or 62, wherein the subject is with seitan sensitivity, gluten or chyle It rushes down.
64. the method according to any one of claim 56 to 59 or 63, wherein the chylous diarrhea is intractable.
65. a kind of for inhibiting with seitan is sensitive or one kind of gluten and the exposure of the seitan of subject in need or more The method of kind symptom, the method includes applying to the subject according to claim 1 to antibody described in any one of 54.
66. method according to claim 65, wherein one or more symptoms include courbature, somatalgia, joint Bitterly, fatigue, aerogastria, intestines gas, nausea, colic pain, constipation, diarrhea, fash, headache, migraine, depression and anxiety, brain mist and tired It is one of hot-tempered or a variety of.
67. the method according to any one of claim 56-66, wherein the subject eats diet containing seitan.
68. a kind of method for the rheumatoid arthritis for treating subject in need, the method includes to the subject Application is according to claim 1 to antibody described in any one of 54.
69. a kind of method for the psoriasis for treating subject in need, the method includes applying basis to the subject Antibody described in any one of claim 1 to 54.
70. a kind of method for the inflammatory bowel disease for treating subject in need, the method includes applying root to the subject According to antibody described in any one of claim 1 to 54.
71. a kind of method for the type 1 diabetes for treating subject in need, the method includes applying root to the subject According to antibody described in any one of claim 1 to 54.
72. a kind of method for the alopecia areata disease for treating subject in need, the method includes applying basis to the subject Antibody described in any one of claim 1 to 54.
73. a kind of method for the T cell large granular lymphocyte leukaemia for treating subject in need, the method includes It applies to the subject according to claim 1 to antibody described in any one of 54.
74. a kind of method for the autoimmune disease for treating subject in need, the method includes to the subject Application is according to claim 1 to antibody described in any one of 54.
75. method according to claim 74, wherein the autoimmune disease is the autoimmune of IL-15 imbalance Disease.
76. a kind of method of inflammatory disease for treating or inhibiting subject in need or inflammatory condition, the method includes to Subject's application is according to claim 1 to antibody described in any one of 54.
77. the method according to claim 76, wherein the inflammatory disease or inflammatory condition are the inflammatory diseases of IL-15 imbalance Disease or inflammatory condition.
78. the method according to any one of claim 56 to 77, wherein the antibody is comprising pharmaceutically acceptable In the composition of carrier or excipient.
79. being used to treat chylous diarrhea, intractable chylous diarrhea, class wind to antibody described in any one of 54 according to claim 1 Wet arthritis, psoriasis, inflammatory bowel disease, type 1 diabetes, alopecia areata disease, T cell large granular lymphocyte leukaemia, itself The inflammatory disease of immunity disease, autoimmune disease, inflammatory disease or the inflammatory condition of IL-15 imbalance or IL-15 imbalance Or inflammatory condition.
80. being used to treat or inhibit one kind or more of seitan exposure to antibody described in any one of 54 according to claim 1 Kind symptom.
81. being used to manufacture the use of the drug for treating following disease to antibody described in any one of 54 according to claim 1 On the way: chylous diarrhea, intractable chylous diarrhea, rheumatoid arthritis, psoriasis, inflammatory bowel disease, type 1 diabetes, alopecia areata disease, T cell Large granular lymphocyte leukaemia, autoimmune disease, autoimmune disease, inflammatory disease or the inflammation of IL-15 imbalance Property illness or IL-15 imbalance inflammatory disease or inflammatory condition.
82. being used to manufacture the disease for treating or inhibiting seitan exposure according to claim 1 to antibody described in any one of 54 The purposes of the drug of shape.
83. the purposes according to claim 82, wherein the symptom includes courbature, somatalgia, arthralgia, fatigue, stomach One of inflatable, intestines gas, nausea, colic pain, constipation, diarrhea, fash, headache, migraine, depression and anxiety, brain mist and agitation Or it is a variety of.
84. a kind of for detecting the in-vitro method of the IL-15 from the tissue sample that subject separates, the method includes making root It contacts according to antibody described in any one of claim 1 to 54 with the tissue sample separated from subject to form antibody-and IL- The compound in the compound IL-15 of 15 receptor alphas, and the detection tissue sample.
85. a kind of for detecting the external of the compound of the IL-15 and IL-15 receptor alpha from the tissue sample that subject separates Method, the method includes making the tissue sample that antibody described in any one of -54 is separated with from subject according to claim 1 Contact is to form the Antibody-antigen complex of the antibody Yu IL-15 and IL-15 receptor alpha, and detects in the tissue sample The Antibody-antigen complex.
86. a kind of cell of conversion is expressed according to claim 1 to antibody described in any one of 54.
87. the cell of the conversion according to claim 86, wherein the cell is mammalian cell.
88. the cell of the conversion according to claim 87, wherein the mammalian cell is Chinese hamster ovary cell.
89. a kind of method of antibody of generation as described in any one of claim 1-54, the method includes cultures such as right It is required that cell described in any one of 86-88.
90. a kind of polynucleotides, it includes the nucleic acid sequence of encoding antibody variable heavy chain, the antibody variable heavy-chain includes SEQ The amino acid sequence of ID NO:1.
91. the polynucleotides according to claim 90, wherein the nucleic acid sequence encoding antibody variable heavy-chain, the antibody Variable heavy chain includes the amino acid sequence of SEQ ID NO:4.
92. the polynucleotides according to claim 90 or 91, wherein the polynucleotides also include encoding antibody light can Become the second nucleotide sequence in area, the antibody's light chain variable region includes the amino acid sequence of SEQ ID NO:2.
93. the polynucleotides according to claim 92, wherein the second nucleotide sequence encoding antibody variable light, described Antibody variable light chain includes the amino acid sequence of SEQ ID NO:5.
94. a kind of polynucleotides, it includes the nucleic acid sequence of encoding antibody variable light, the antibody variable light chain includes SEQ The amino acid sequence of ID NO:2.
95. a kind of polynucleotides, it includes the nucleic acid sequence of encoding antibody variable light, the antibody variable light chain includes SEQ The amino acid sequence of ID NO:5.
96. a kind of polynucleotides, it includes the nucleic acid sequences of coding antibody according to any one of claim 5 to 54.
97. a kind of polynucleotides, it includes the nucleic acid sequences of SEQ ID NO:517.
98. a kind of polynucleotides, it includes the nucleic acid sequences of SEQ ID NO:518.
99. a kind of carrier, it includes the polynucleotides according to any one of claim 90 to 98.
100. a kind of cell is transfected with the carrier according to claim 99.
101. a kind of cell, it includes the cores of the variable heavy chain of the antibody containing coding as described in any one of claim 1-54 The polynucleotides of the nucleic acid of the polynucleotides and variable light containing encoding said antibody of acid.
102. the cell as described in claim 101, wherein encoding the nucleic acid of the variable heavy chain and encoding described variable The nucleic acid of light chain is on the same vector.
103. the cell as described in claim 102, wherein encoding the nucleic acid of the variable heavy chain and encoding described variable The nucleic acid of light chain is different carrier.
104. cell described in any one of 00-103 according to claim 1, wherein the cell is mammalian proteins expression Cell.
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